# Microbial Biosynthesis of Lactones: Gaps and Opportunities towards Sustainable Production
## 2 Properties, Diversity and Applications/Chemistry and Applications  
As mentioned, lactones are cyclic carboxylic esters, which can derive from intramolecular esterification of carboxylic acids. Lactones present two common structural traits: the presence of a (\(-\)C(=O)\(-\)O\(-\)) carboxylic ester group and a cyclic ring organization, which can have heteroatoms, substitutions or unsaturations in the ring structure. Lactones have a variable number of carbons, and nomenclature often refers to the carboxylic acid precursor, with the total number of carbons in the molecule represented before the -lactone suffix, e.g., carbon atoms: 2-aceto, 3-propio and 4-butyro. Another key structural parameter in lactones is the number of atoms participating in the cyclic ring. This is noted in lactone nomenclature by including the prefix of \(\alpha\)- (three atoms in the cyclic ring), \(\beta\)- (four atoms in the cyclic ring), \(\gamma\)- (five atoms in the cyclic ring) and \(\delta\)- (six atoms in the cyclic ring) [1]. Among these, \(\gamma\)- and \(\delta\)- are the more stable forms of lactones, and thus the main focus of most processes and applications [5]. For example, as reported for \(\gamma\)-decalactone, its conformation is so stable that cyclization of 4-hydroxydecanoic acid occurs spontaneously at room temperature in the presence of dilute acids [25].  
Lactones can be naturally found in different organisms, either in bacteria, yeast, plants and vertebrates, and are reported to be motifs used by organisms to communicate via the chemical channel [15; 26]. For example, lactones are commonly found in fruits (e.g., strawberries, peaches and pineapples), where they act as signals for attracting feeders to promote pollination and seed dispersion [22]. Thus, these compounds are naturally potent flavoring agents which translate into their main application. Different lactones have different associated aroma descriptors, from which \"fruity\", \"peach\", \"coconut\" and creamy can be highlighted. Therefore, these compounds are very sought-after in food and cosmetic industries, to be used as pure fragrances and/or flavors in the most diverse formulations.  
Apart from aroma applications, lactones can also be used in alternative products and commodities: biodegradable polymers for use in medical devices (e.g., polycaprolactone) [27]; green/non-toxic solvent alternatives; and drop-in agents in the production of C8 alkanes (used in jet fuel), C9 and C18-C27 alkanes (gasoline and biodiesel) and other polymers. Such is the example of \(\gamma\)-valerolactone, a highly promising compound for generating energy and producing carbon-based commodities, which can furthermore be sourced from sustainable and renewable resources [16; 28]. Lastly, macrolide antibiotics (erythromycin, azithromycin) are also lactones, more specifically macrocyclic lactones with high structural complexity and a broad range in the management of infectious diseases [13; 29].  
Chemical synthesis of lactones can be promoted by different reaction mechanisms, for example from carboxylic acids by Yamaguchi esterification [30], Shiina macrolactionization [31] or Corey-Nicolaou macrolactionization [32] and from ketones by Baeyer-Villiger oxidation [33]. Most of these reactions involve the use of acids (e.g., Lewis acids), pyridines (e.g., DMAP) and/or oxidants (e.g., peroxide), either as reactants or catalysts, in addition to the precursors. Thus, utilization of unsustainable and environmentally dangerous reactants is inherent and several works have strived for greener alternatives for lactone production, either via chemical synthesis or biotechnological alternatives. The latter will be explored in more detail in this review.