NPR REVIEW View Article Online View Journal | View Issue The use of the lactone motif in chemical communication Cite this: Nat. Prod. Rep.,2015,32, 1042 Stefan Schulz* and Susann Hotling¨ Covering: up to 2014 A wide variety of organisms communicate via the chemical channel using small molecules. A structural feature quite often found is the lactone motif. In the present paper, the current knowledge on such lactones will be described, concentrating on the structure, chemistry, function, biosynthesis and synthesis of these compounds. Lactone semiochemicals from insects, vertebrates and bacteria, Received 20th January 2015 which this article will focus on, are particularly well investigated. In addition, some ideas on the DOI: 10.1039/c5np00006h advantageous use of lactones as volatile signals, which promoted their evolutionary development, will be Creative Commons Attribution 3.0 Unported Licence. www.rsc.org/npr discussed. 1 Introduction 2 Small ring lactones 3 Five- and six-membered ring lactones 4 Larger macrocyclic lactones 5 Terpenoid lactones 6 Aromatic lactones This article is licensed under a 7 Bacterial signals 8 Discussion 9 Conclusion Fig. 1 Calculated values† of the octanol/water partition coefficient 10 Acknowledgements (log D), boiling point (bp), and vapour pressure (vp) of hydroxy acid 1 Open Access Article. Published on 15 May 2015. Downloaded 10/2/2021 2:34:47 AM. 11 References and its cyclization product 2. But which compounds are actually active information 1 Introduction transfer entities? Unfortunately, especially the chemical Chemical communication is one of the major factors shaping synthetic literature is sometimes misleading when biological ff our environment by the actions of organisms. Although prob- e ects are described. For example, (S)-4-hexanolide has been ably less important to humans compared to other senses, most repeatedly synthesized and claimed to be a pheromone of Tro- other organisms rely heavily on their chemical sense. This is goderma beetles, important pests of stored products. Though exemplied especially in insects, on which most research has correctly identi ed, no function of the compounds in chemical 4,5 been focused, driven by their economic importance. But communication has ever been proven. The sex pheromone of chemical compounds used for the transmission of information various Trogoderma sp. is indeed (Z)- and/or (E)-14-methyl-8- (semiochemicals), have also been characterized in other hexadecenal. This example underlines the need for critical arthropods, mammals, plants, shes, fungi, bacteria and so on. evaluation of the literature. Examples can be found in various other articles of this issue. If In our review we will present the structures and functions of ff one looks at all the compounds currently known, e.g. in lactones used in chemical communication systems by di erent insects1,2 or bacteria,3 a structural feature repeatedly occurring organisms. We will focus mostly on insects and bacteria, is the lactone motif. Forty of the 436 structures listed in a recent because many lactones are used by these organisms. But before overview on arthropod pheromones are lactones.2 doing so, a short discussion will show why this motif is a “privileged structure” for communication in nature. Institute of Organic Chemistry, Technische Universitat¨ Braunschweig, 38106 Braunschweig, Germany. E-mail: [email protected].; Tel: +49 531 3917353 † The values were calculated using ACDLabs soware. 1042 | Nat. Prod. Rep.,2015,32,1042–1066 This journal is © The Royal Society of Chemistry 2015 View Article Online Review NPR Lactones are cyclic esters of hydroxy acids. Hydroxy acids or 2 Small ring lactones their activated forms are usually the natural precursors in the biosynthesis of lactones. Fig. 1 shows some calculated values Only a few semiochemicals with a b-propiolactone ring have of physical constants of 5-hydroxypentanoic acid (1)andits been described. Vittatalactone (9) and its minor nor-derivative cyclization product, lactone 2.Withcyclization,thevapour 16 have been isolated from the striped cucumber beetle, Aca- pressure rises by a factor of 100 and the boiling point lymma vittatum (Coleoptera: Chrysomelidae).7 These male decreases. The lactone is, therefore, much better suited to specic compounds show electrophysiological activity in serve as a volatile chemical signal than the hydroxy acid. antennae of both sexes, and were suggested to act as an Similarly, the octanol/water partition coefficient rises by a aggregation pheromone,7,8 but no behavioural studies have factor of 1000. Therefore, the passage through lipophilic been reported. The absolute conguration shown has been membranes without a transporter is easier for 2 than 1, deduced by total synthesis of the enantiomers.9,10 Breit et al. making the former better suited as a general signal trans- developed a highly efficient synthesis starting from meso- porter. Furthermore, the hydroxyacidislargelydeprotonated anhydride 3. Lipase catalysed desymmetrization led to 4 which at physiological pH, further increasing the hydrophilicity and was further transformed into the bromide 5. The respective decreasing the vapour pressure. copper reagent introduced the next stereogenic centre by Another relevant aspect seems to be the short biosynthetic enantioselective allylic substitution, guided by the voluminous transformation needed to get from 1 to 2. The signal precursor, i.e. o-diphenyl-phosphinobenzoyl group. The allylic alcohol 6 was the hydroxy acid, can be stored, e.g. in a pheromone gland, until it subjected to Sharpless epoxidation. Epoxide opening by a is needed. A simple cyclization, probably aer activation of the methylcopper reagent led to alcohol 8 which was further acid group, furnishes the lactone, ready for it to leave the gland or transformed into 9 via the hydroxy acid and lactonization by cell. The cyclization of 1 is also entropically favourable. Finally, tosyl chloride (Fig. 2).10 The synthesis comprised 11 steps with inactivation of the signal, an important process following an overall yield of 18%. Schneider et al. used the Evans aldol Creative Commons Attribution 3.0 Unported Licence. perception, can be readily achieved by simple hydrolysis via product 10 as the precursor for a Cope rearrangement to enzymes. Nevertheless, in some cases hydroxy acids serve as synthesize 11.Aer stereoselective introduction of the C-2 pheromone components themselves, without concomitant lactone methyl group (12) and iridium catalysed enantioselective formation, e.g. (E)-9-hydroxydec-2-enoic acid, a component of the hydrogenation of the enol ether group, followed by additional queen retinue pheromone of the honey bee, Apis mellifera.6 functional group manipulation, furnished 13 that was elon- Most of the lactones discussed here originate from fatty acid gated by Grignard chemistry. A chiral auxiliary aldol conden- biosynthesis, but other biosynthetic pools are also used. These sation to form 15 set the stage for a nal auxiliary cleavage and comprise polyketides, amino acids, and terpenes. In the tosyl chloride mediated lactonization to give 9.11,12 Norvittata- following chapters, selected different signalling lactones will be lactone 16 was obtained via the same route (Fig. 3).12 Finally, a This article is licensed under a described and their occurrence, function, and biosynthesis as desymmetrization and auxiliary-controlled asymmetric alkyl- well as their synthesis will be described, focusing on the last 20 ation strategy was used to obtain both enantiomers of 9.13 years. Although no studies on the biosynthesis of b-lactones have Open Access Article. Published on 15 May 2015. Downloaded 10/2/2021 2:34:47 AM. been performed, it seems likely that they are formed via a fatty Prof. Dr. Stefan Schulz studied Susann Hotling¨ studied chemistry chemistry at the University of at the Technische Universitat¨ Hamburg, Germany. He Braunschweig, Germany. Her received his PhD under the diploma thesis focused on the guidance of Prof. Wittko identication and synthesis of Francke. In 1988, he took up a macrolide pheromones of the postdoctoral position with Prof. grain beetle, Oryzaephilus sur- Jerrold Meinwald at Cornell inamensis, under the guidance of University, Ithaca, USA, eluci- Prof. Stefan Schulz. Since 2010, dating the biosynthesis of she has been working on her PhD pheromones derived from pyr- in the Schulz work group. Her rolizidine alkaloids. Aer research interest is the identica- returning to Hamburg, he tion and synthesis of lactones and worked on his habilitation, focusing on spider pheromones. In terpenes as pheromones in insects 1997, he became Full Professor of Organic Chemistry at the and amphibia. Technische Universitat¨ Braunschweig. His major research areas are the identification, synthesis, biosynthesis, and function of signaling compounds released by diverse organisms, including bacteria, invertebrates and vertebrates. This journal is © The Royal Society of Chemistry 2015 Nat. Prod. Rep.,2015,32,1042–1066 | 1043 View Article Online NPR Review Fig. 2 Breit's synthesis of vittatalactone (9).10 o-DPPB: o-diphenylphosphinobenzoyl; TBDPS: tert-butyldiphenylsilyl. acid biosynthesis pathway employing propionate (methyl- The PAs ingested by the butteries are cleaved to liberate the malonate) building blocks as the source of the methyl branches. b-lactone precursors virdioric acid and norviridioric acid (21, A precursor acid such as 3-hydroxypentamethyl-undecanoic 22), which are then cyclized (Fig. 4). Biosynthetic studies on the acid is then