Synthesis of Macrocyclic Dilactones through Lipases

Abstract

We report herein a selective and efficient method to prepare macrocyclic dilactones in good yields from diols and succinic anhydride through a biocatalytic condensation reaction.The synthetically challenging structures of macrolides have attracted the attention of organic chemists for a long time but only recently have efforts in this direction begun to gain momentum. 1 Particularly attractive are macrocyclic dilactones, not only because of their remarkable biological activities but also because of their ability to complex and transport alkali metal cations and their utilization in the perfume industry. 2 However, only a limited number of methods for preparation of macrocyclic dilactones are currently available. They comprise the reaction of the dicesium salts of pyridindicarboxylic acids with dibromides, 3 reaction of dioxodioic acid chlorides with oligoethylene glycols, 4 condensation of the dipotassium salt of maleic, citraconic and o-phthalic acids with alkyl or alkynyl dibromides, 5 condensation of benzyl bromides with homologous series of dicarboxylic acids, 6 reaction of substituted dicarboxylic acid chlorides with w-bromoalcohols followed by reaction with lithium or potassium salts of dicarboxyxlic acids, 7 condensation of diacid chlorides with diols using metal carbonates and KF as bases under phase-transfer catalysis, 8 or via cyclization of (wcarboxyalkyl)diphenylsulfonium salts in the presence of cesium carbonate under high dilution conditions. 9 However, many of these methods provide mixtures of dilactones and tetralactones, in some cases in low yields and under harsh reaction conditions. Only one case has been found in the literature in which macrocyclic lactones are prepared enzymatically by reaction of acyclic diacids with diols in the presence of C. cylindracea, Pseudomonas sp. and porcine pancreatic lipase. 10 However, even in this case mixtures of mono-and dilactones were obtained in moderate yields, the dilactones being produced in the range of 5-19% yield.In this paper we present a simple and high yielding method to selectively prepare macrocyclic dilactones by reaction of 1,n-diols with succinic anhydride 11 in the presence of Candida Antarctica B lipase (CALB, Novozyme 435). Intramolecular lactonization of long chain hydroxyesters with lipase P (Pseudomonas sp.) to provide pheromone components of grain beetles 12 or a key intermediate for the synthesis of the anti-obesity agent tetrahydrolipstatin with PPL has been described. 13 Initially, we tested the reaction of 1,6-hexanediol and succinic anhydride in the presence of several lipases (PS, AP-6, Mucor miehei, Candida rugosa, CALB and Pseudomonas fluorescens) in a number of solvents and under different experimental conditions. Scheme 1 Enzymatic reaction of diol 1d with succinic anhydride 2The reaction resulted in a mixture of variable amounts of starting diol 1d, hydroxyacid 3d, dilactone 4d and diacid 5d 14 (Scheme 1) by GC analysis after esterification with MeI/K 2 CO 3 . 15 Under these conditions, compounds 3d and 5d are converted into...

New Approach to the Synthesis of Macrocyclic Tetralactones via Ring-Closing Metathesis Using Grubbs' First-Generation Catalyst

“…Many macrolides have been ingeniously approached by RCM methods . Synthesis and studies of the macrocyclic dilactones are impressive in organic chemistry due to their biological properties, complex formation, ion carriers, and application in the perfume industry. Even though literature methods provide a mixture of dilactones and tetralactones, the reactions give low yields and require drastic conditions.…”

Desymmetrization of Cyclic Anhydrides Using Dihydroxy Compounds: Selective Synthesis of Macrocyclic Tetralactones

“…These methods involve the reaction of the dicesium salts of acids with dibromides, reaction of acid chlorides with glycols, condensation of dipotassium salt of acids with dibromides, condensation of dicarboxylic acids with benzyl bromides, reaction of acid chlorides with ω-bromo alcohols, condensation of diacid chlorides with diols under phase-transfer catalysis, cyclization of sulfonium salts in the presence of cesium carbonate, or the reaction assisted by alkaline metals . Recently, synthesis of dilactones was also reported through lipase catalysis or photochemical acylation . Even though methods available in the literature provide a mixture of dilactones and tetralactones, the reactions give low yields and require drastic conditions.…”