Mass Spectrometry of Aliphatic Macrolides, Important Semiochemicals

Review pubs.acs.org/jnp

Mass Spectrometry of Aliphatic Macrolides, Important Semiochemicals or Pheromones Stefan Schulz,* Pardha Saradhi Peram, Markus Menke, Susann Hötling, Rene Röpke, Kristina Melnik, Dennis Poth, Florian Mann, Selma Henrichsen, and Katja Dreyer Institute of Organic Chemistry, Technische Universität Braunschweig, Hagenring 30, 38106 Braunschweig, Germany S Supporting Information *

ABSTRACT: Macrolides are a relatively common structural motif prevalent in Nature. However, the structures of these large ring lactones have been relatively difficult to elucidate via NMR spectroscopy due to the minute amounts of compounds that are sometimes obtainable from natural sources. Thus, GCMS analysis of individual macrolactones has become the method of choice for the structural identification of these compounds. Here we discuss the mass spectrometric behavior of aliphatic macrolides, evaluating spectra from numerous compounds of various ring size, including derivatives containing methyl branches as well as double bonds. The specific fragmentation of these macrolactones under electron impact conditions allows for the development of a general rule set aimed at the identification of similar compounds by mass spectrometry. In addition, the mass spectra of dimethyl disulfide adducts of unsaturated macrolides are discussed. The mass spectra of almost 50 macrolides are presented.

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that would allow for structural proposals of unknown macrolides to be made. Herein are presented results based on mass spectra acquired in our laboratory, and an attempt has been made to develop a set of rules for the structural elucidation of macrolides based on proposals for fragmentation and backed up by high-resolution mass spectrometric data for key fragments. In addition, mass spectra of macrolactones have been explored either published in the literature or else were easily obtained from mass spectrometric databases.6 In the following text, a number of shorthand terms have been utilized to make the discussion easier to read. The carbon of the CH−O bond is termed the terminal end of the macrolide. We will also use the name of a compound as a shorthand for its mass spectrum and the figure (sub)number of the mass spectrum as compound number. Mass spectra of diastereomeric macrolides are usually quite similar, as are the spectra of double bond isomers, at least for the few examples for which both spectra were available. Therefore, stereogenic descriptors have been omitted for ease of discussion. The structures are provided in the Supporting Information.

acrolides, large ring lactones, constitute a structural motif often found among natural products. Highly functionalized macrolides are formed by various organisms and are often associated with important biological functions, for example, antibiotic activity or cytotoxicity. In contrast, nonfunctionalized aliphatic saturated and unsaturated macrolides, derived biosynthetically from the fatty acid or terpene pathway, are frequently used as semiochemicals.1 For example, various macrolides ranging in ring size from 10 to 24 act as pheromones in butterflies, bees, or beetles,1 are aroma components of plants,2 or are released by microorganisms.3 The identification of such macrolides is sometimes difficult because they often occur in trace amounts and as components of complex mixtures, making isolation and investigation by NMR spectroscopy very difficult and time-consuming. Therefore, GC/MS is the method of choice for their analysis. Nevertheless, the electron impact (EI) mass spectra of macrolides are difficult to interpret.4 Contrary to open-chain compounds like aliphatic alcohols, ketones, or esters, an initial cleavage will not break the molecule into two parts but will only result in rearranged charge and radical locations, giving rise to multiple pathways for secondary fragmentation. Aliphatic openchain compounds can be structurally analyzed by well-defined fragmentation rules,5 while such rules currently do not exist for macrolactones. During our synthetic work with natural macrolides from different communication systems, a large variety of mass spectra were obtained, showing potential for indepth analysis to explore whether a rule set can be established © 2017 American Chemical Society and American Society of Pharmacognosy

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MASS SPECTROMETRIC OBSERVATIONS Aliphatic macrolides (ring size >9) often display ambiguous mass spectra. How can one be sure that a mass spectrum really represents a macrolide? While this is relatively easy for smaller Received: April 26, 2017 Published: August 24, 2017 2572

DOI: 10.1021/acs.jnatprod.7b00366 J. Nat. Prod. 2017, 80, 2572−2582

Journal of Natural Products

Review

Scheme 2. Formation of Characteristic Ions C (blue) and D (turquoise), with the Latter Being Absent in Macrolides

Figure 1. Mass spectra of 16-hexadecanolide (A), 18-octadecanolide (B), and oleic acid (C). Brown arrows indicate A ions and green arrows B ions, both useful for macrolide detection. Their formation is shown in Scheme 1.

Scheme 1. Common Mass Spectrometric Fragmentation Characteristic for Macrolidesa Figure 2. Mass spectra of 4-decanolide (A), 5-decanolide (B), 6decanolide (C), and 9-decanolide (D).

Macrolides elute as sharp peaks, while acids tend to tail, although their retention indices are relatively similar. In general, the brown and green color coded ions in Figure 1 are characteristic for macrolides. The loss of water from M+ is observed,4,7 often accompanied by a second water loss of low intensity, leading to M+-36 (B and B′, green). The McLafferty rearrangement leads to the ions m/z 60 (A) and 73 (A′) as shown in Scheme 1. An M-60 ion (A″) can also be observed.4,7 • A macrolide can be identified by the characteristic ions A (m/z 60, 73, and M-60) and B (M-18, M-36). Careful differentiation from the spectra of related free fatty acids is necessary. Ring Size of Saturated Macrolides. The ring size of lactones with an unbranched carbon chain can be deduced by the dominant α-cleavage next to the ring (C, blue, Scheme 2), accompanied by an even rearrangement ion (D, turquoise, Scheme 2). Various decanolide mass spectra are shown in Figure 2. While ions C, m/z 85, 99, and 113, indicate the ring size in 4-, 5-, and 6-decanolides (Figure 2A−C), its intensity decreases with increasing ring size. The second characteristic lactone ion D, m/z 100, 114, and 128 in Figure 2A−C cannot be formed in 9-decanolide (Figure 2D) and is also absent in larger rings. It does not occur in the spectra of several octadecanolides shown in Figure 3. Nevertheless, ions C are

In the mass spectra shown in the figures the ions A are indicated by brown arrows, while ions B are indicated by green arrows.

a

lactones with 5−7-membered rings, it is often not the case for macrocyclic lactones. At first glance, the mass spectra of large, unbranched macrolides are very similar to those of unsaturated acids, that is, in the case of 18-octadecanolide (Figure 1B) and oleic acid (Figure 1C). These spectra are very similar because an initial McLafferty rearrangement of 18-octadecanolide will lead to an unsaturated acid (Scheme 1), for which the further fragmentation is very similar to that of octadecenoic acids. Nevertheless, there are subtle differences, such as a lower abundance of m/z 45 and matching intensities of the ions M+ and M+-18 in the macrolide (Figure 1B,C). An additional hint is the gas chromatographic behavior on apolar columns. 2573



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Scheme 4. Formation of Characteristic Ion F via E

series CnH2nO, determined by HRMS data, and are formed by loss of an aldehyde from the ester group, most probably via the pathway shown in Scheme 3 for 11-octadecanolide. Ionization at the ring oxygen will initiate cleavage to form the distonic ion E (red) and a neutral aldehyde. Again, the intensity of the ion decreases with length of the exoalkyl chain, but usually it is easily found in spectra of saturated macrolides, as the spectrum of 17-octadecanolide (m/z 238, Figure 3D) shows. Ions D and E are a reliable and significant ion pair that allow unequivocal determination of the ring size in fatty acid- or terpene-derived macrolides. They are not present in unsubstituted macrolides (Figure 1B and various published spectra such as 12dodecanolide,6 13-tridecanolide,8 14-tetradecanolide,8 15-pentadecanolide,6,8 16-hexadecanolide8). The ion can also be found besides C in the spectrum of 13-(1-methylpropyl)tridecanolide,9 15-hexadecanolide,6,8 14-pentadecanolide,6 13tetradecanolide,6,8 and 11-dodecanolide.8 It has to be noted that the NIST library shows an incorrect spectrum of 14tetradecanolide (NIST# 99130), which is actually 13tetradecanolide.6 • The ring size and the terminal substituent can be determined in saturated macrolactones by the ions C and E. The ring size depends also on the substituents in the ring. Methyl Branched Saturated Macrolides. Recently, fatty acid-derived macrolides bearing methyl groups along the chain have been detected.10 Synthetic libraries of methylated 9decanolides and 11-undecanolides were prepared, allowing some insight into their mass spectrometric behavior. The mass spectra of 2-, 4-, 6-, and 8-methyldecan-9-olide,10 as well as 2-, 4-, 6-, 8-, and 10-methyldodecan-11-olide,11 possess a prominent peak either at m/z 98 (C6H12O determined by HRMS) or at m/z 112 (C7H14O), being by far the most important even ion. We propose that these ions are likely formed by a pathway leading to the ion F (Scheme 4, violet) that is able to form a well-stabilized six-membered ring. The mass spectra of 6-methyl-9-decanolide10 and 6-methyl-11dodecanolide are shown in Figure 4E,F. The former fragments into ion E as described, which upon release of neutral ethene

Figure 3. Mass spectra of 11-octadecanolide (A), 12-octadecanolide (B), 13-octadecanolide (C), and 17-octadecanolide (D).

Scheme 3. Formation of the Characteristic Ion E That Determines Macrolide Ring Size

prominently present, allowing determination of the ring size, but lose intensity when the terminal alkyl substituent becomes small. Both 9-decanolide (Figure 2D) and 17-octadecanolide (Figure 3D) mass spectra exhibit only small ions C. A second type of ion indicating ring size are the intense ions E, m/z 154, 168, and 182, in the spectra of 11-, 12-, and 13octadecanolides (Figure 3A−C). These ions belong to the 2574



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Figure 4. Mass spectra of 2-methyl-9-decanolide (A),10 2-methyl-11-dodecanolide (B),11 4-methyl-9-decanolide (C),10 4-methyl-11-dodecanolide (D),11 6-methyl-9-decanolide (E),10 6-methyl-11-dodecanolide (F),11 8-methyl-9-decanolide (G),10 8-methyl-11-dodecanolide (G),10 and 10methyl-11-dodecanolide (I).11

can form ion F at m/z 112, as shown in Scheme 4. Similarly, ion E derived from the larger dodecanolide expels C4H8, for example, by subsequent release of two ethene units, to form the same ion F. Ion F is found at m/z 98 when C-1 to C-6 are unsubstituted, at m/z 112 when the structure carries one methyl group, or at m/z 126 when the structure carries two methyl groups. The ion m/z 84 (C6H12) sometimes observed (Figure 2D) does not belong to the ion series F because of its composition. The only exception observed so far are 2-methylalkanolides that

show both m/z 98 and 112 (Figure 4A,B). Nevertheless, they can be easily identified because the ions A/A′ now shift to m/z 74 and 87, occurring with pronounced intensity. This shift locates a methyl group at C-2. A methyl group at C-3 leads to m/z 60 and 87 (Figure 5B). Finally, the unique ion m/z 114 (C6H10O2) occurs only in 4-methyl substituted macrolides (Figure 4C,D). Its formation can be explained by α-cleavage next to the ring oxygen, followed by expulsion of cyclobutane (4-methyl-9-decanolide)10 or even more stable cyclohexane (4methyl-11-dodecanolide). Ion m/z 114 is stabilized by the six2575



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Scheme 6. Formation of Ions G and G′, Allowing Localization of the Double Bond Position in Monounsaturated Macrolidesa

Figure 5. Mass spectra of 2,6,10-trimethyl-11-undecanolide (A) and 3,7,11-trimethyl-12-dodecanolide (B).

Scheme 5. Formation of Ion m/z 114 in 4-Methylalkanolides (n = 1, 3)

a

An alternative mechanism starting with ionization at the double bond is also possible.13

membered ring, the oxonium ion, and the secondary radical (Scheme 5). These factors are only present in 4-methylsubstituted macrolides. The ions E are always present, although sometimes in low abundance. Their intensity is enhanced when a secondary radical is formed, as in the case of 8-methyl-9decanolide (Figure 4G) and 10-methyl-11-dodecanolide (Figure 4I). Ions E and C occur in varying intensity, sometimes supported by additional loss of water (M-18−15). The mass spectrum of 12-methyl-13-tridecanolide6 shows an enhanced M-30 (E) and m/z 98 (F), in line with the previous discussion. The rules discussed can be used to assign structural features of unknown compounds. Figure 5 shows the spectra of 2,6,10trimethyl-11-undecanolide (A) and 3,7,11-trimethyl-12-dodecanolide (B). The spectrum of the first compound did not show any ions C or E, indicating an unsubstituted terminal CH2−O group. Ions A m/z 74 and m/z 87 indicate a C-2 methyl group, while m/z 126 (F) places a second methyl group between C-3 and C-6. Its position is likely not at C-4 because of the absence of a m/z 114/128 ion, leaving C-6 as the most likely one. No clear proof for the C-10 methyl group can be found. Similarly, ions A derived from 3,7,11-trimethyl-12-dodecanolide can be found at m/z 60 (low abundance) and 87, characteristic for a C-3 methyl group. Ion F is the largest even-numbered ion at

Figure 6. Mass spectra of 5-tetradecen-13-olide (A) and 9-tetradecen13-olide (B).13

m/z 112. Therefore, no additional methyl group is present between C-2 and C-6. The methyl groups at C-7 and C-11 cannot be located easily. • The presence and position of methyl groups located between C-2 and C-6 of the chain can be deduced by analyzing ions A and F in saturated macrolides. Unsaturated Macrolides. Mass spectra of mono- and diunsaturated macrolides are similar in appearance to those of the respective free di- and triunsaturated acids.12 The ions E for the determination of the ring size are not formed anymore, while ions A and B are of low abundance. The ring size is hard to detect, because ion C is often only formed in minor amounts, especially when the alkyl substituent is a methyl group or ethyl group. Nevertheless, a new fragmentation occurs, leading to ions G (orange, Scheme 6), which determine 2576



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most intense in the ion series CnH2n−4O2. Ion G′ cannot be formed in 9-tetradecen-13-olide (Figure 6B), but ion G occurs at m/z 182. Figure 7 shows mass spectra of some octadecenolides, exemplifying the scope and limitation of the diagnostic value of G. Terminally unbranched lactones such as 9-octadecen-18olide, 7-hexadecen-16-olide (ambrettolide),6,8or 2,6-dimethylundec-6-en-11-olide14 often do not show ions G with significant intensity, in contrast to its isomer 9-octadecen-17olide, likely because the initially formed distonic radical ion is less stable compared to branched isomers. The length of the terminal substituent is unimportant, as seen by 9-octadecen-13olide. If this substituent moves into the allyl (9-octadecen-11olide) or homoallyl position (9-octadecen-12-olide), the ions G loss their diagnostic value. If the double bond moves closer to the carbonyl group, fragmentation changes. Alk-4-enolides show a prominent ion m/z 113 (G+1, C6H9O2), accompanied by the G′ ion m/z 126, exemplified by 4-decen-9-olide (phoracantholide J, Figure 8A).16 The ions G can also be observed in methyl-branched macrolides, which are sometimes shifted according to the position of the methyl group. 8-Methyldec-4-en-9-olide (Figure 8B) shows the prominent ion pair m/z 113/126, which is shifted to m/z 127/140 in 6-methyldec-4-en-9-olide (Figure 8C). 8-Methyldodec-4-en-11-olide (Figure 8D) shows the expected G pair at m/z 113/126, while m/z 140/154 are the values for 4-methyldodec-5-en-11-olide (Figure 8E) because of the additional methyl branch in G. Mass spectra of alk-3enolides, for example, 3-dodecen-11-olide (ferrulactone II, Figure 8F) do not show the ions G in enhanced intensity.17,18 Careful analysis of a published spectrum of docosenolide4 indicates the double bond to be located at C-13, because of the small G pair at m/z 238/252. Although the ion E is absent in unsaturated macrolides, the terminal side chain length can often been deduced from C (see blue arrows in Figures 6−8). This ion is usually enhanced compared to homologues within the ion series CnH2n−1O in unsaturated macrolides. Nevertheless, one has to keep in mind that most unsaturated macrolides form a M-29 ion (M-C2H5) of unclear origin, regardless of the branching pattern or ring size. In 8-methyldodec-4-en-11-olide (Figure 8D), this ion, m/z 181, occurs with higher abundance when compared to ion C. • The position of a double bond in monounsaturated macrolides can be deduced by ions G, provided the double bond is located not closer than C-4 to the carbonyl group and not in an allyl- or homoallyl-position relative to the terminal C−O bond. Diunsaturated Macrolides. Diunsaturated macrolides show a different mass spectrometric behavior. Their spectra resemble those of triunsaturated acids, which makes some of them difficult to detect when the mass spectrum is not of high quality.19 Ions G can no longer be observed. Instead, a loss of the two last ring carbons including the terminal substituent can be observed in a series of unbranched and terminally methyland ethyl-branched tetradeca-5,8-dienolides (Figure 9A−C), leading to ion H (pink, Scheme 7).12,19 Obviously, a different reaction pathway is followed compared to monunsaturated macrolides, as allylic or homoallylic position seems to be of minor importance. This may indicate that prior to this fragmentation rearrangement of double bonds occurs, as frequently found in the mass spectra of polyunsaturated aliphatic compounds. While ion H is present in dodeca-3,6-

Figure 7. Mass spectra of 9-octadecen-18-olide (A), 9-octadecen-17olide (B), 9-octadecen-13-olide (C),15 9-octadecen-12-olide (D), and 9-octadecen-11-olide (E).15

the location of the double bond in monounsaturated macrolides.13 The fragmentation is exemplified by 5-tetradecen-13-olide (Figure 7, Scheme 6).13 Initially, a distonic radical cation is formed by C−O bond cleavage, followed by loss of C7H14 to form a stabilized allylic ion G at m/z 126 (C7H10O2). An alternative formation starting from the double bond might also be possible.13 Ion G is often accompanied by the homologue G′, m/z 140 (C8H12O2), the respective homoallylic radical cation. Usually G occurs in higher abundance than G′ and both ions are clearly visible, being the 2577



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Figure 8. Mass spectra of 4-decen-9-olide (A), 8-methyldec-4-en-9-olide (B), 6-methyldec-4-en-9-olide (C), 8-methyldodec-4-en-11-olide (D), 4methyldodec-5-en-11-olide (E), and 3-dodecen-11-olide (F).

dien-11-olide,20 and deca-3,6-dien-10-olide17 it is absent in octadeca-9,12-dien-15-olide (cucojolide XI, Figure 9D).21 It also not found in macrolides such as 3,10-dodecadien-12-olide (parcoblattalactone)22 or octadeca-9,11-dien-13-olide (coriolide, Figure 9E),19 where the location of the double bond prevents its formation. Instead, the ring-size determining ion C occurs again, accompanied by potentially misleading M-29 ion in cucojolide XI (Figure 9D). A stabilization of the terminal alkyl substituent by a double bond, as is the case in octadeca-9,11,15-trien-13olide, increases23 the formation of C, leading to m/z 207 as the base peak (Figure 9E). Methyl branched diunsaturated macrolides are mostly regular or degraded sesquiterpenes, such as 4,8-dimethyl-3,8-decadien10-olide (suspensolide, Figure 10A),24 4,8-dimethyl-4,8-decadien-10-olide (ferrulactone, Figure 10B),25,26 3,7,11-trimethyldodeca-2,6,10-trien-12-olide (niaviolide, Figure 10C),15 or 4,8,12-trimethylpentadeca-4,8,12-trien-15-olide (brassicalactone, Figure 10D).25 All contain no terminal substituent, and an ion H cannot be formed. No clear fragmentation patterns occur in their mass spectra. Interestingly, the appearance of the mass spectra can change dramatically by just moving one double bond one carbon, as can be seen in the isomers suspensolide and ferrulactone. The latter contains a double bond at C-4. The ion m/z 113 (G+1), characteristic for this double bond location, occurs here at m/z 127 because of the C4 methyl group and dominates the spectrum. It can also be found prominently in brassicalactone. Except ions A, no other characteristic fragments occur. Nevertheless, the ion M-68,

typical for an isoprene unit (C5H8), can be found in the spectra of both niaviolide (m/z 166) and brassicalactone (m/z 194). In summary, structural features are difficult to derive from the mass spectra of branched, polyunsaturated macrolides. • The terminal substituent in polyunsaturated macrolides can be deduced by ion H if it is H, methyl, or ethyl. Dimethyl Disulfide Adducts of Unsaturated Macrolides. The adducts of dimethyl disulfide (DMDS) to double bonds are used for the localization of double bonds in various acyclic aliphatic compounds.27−29 These derivatives can be easily formed, even if only small amounts of material are available. In acyclic compounds, the preferred cleavage between the thiomethyl groups indicates the position of the double bond clearly. In macrolides, mass spectra become more complicated, making the interpretation less straightforward. The first mass spectrum reported, the DMDS adduct of docos13-en-22-olide, suggested an initial McLafferty rearrangement ring opening and a cleavage between the thiomethyl groups, leading to characteristic fragments I and K.4 Contrary to openchain compounds, these ions are of low or medium intensity. Nevertheless, the subsequent loss of water and methanethiol leads to intense characteristic ions. The acid-containing ion I at m/z 259 loses water, methanethiol, and one H, leading to the base peak at J m/z 192, while the small ion K m/z 171 similarly loses methanethiol and a H to form ion M m/z 122.4 These ions were used to locate the double bond at C-13. Other prominent ions present, not readably explainable, were m/z 243 (L) and 173. This spectrum was obtained with a sector field 2578



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Figure 9. Mass spectra of tetradeca-5,8-dien-14-olide (A), tetradeca-5,8-dien-13-olide (B), tetradeca-5,8-dien-12-olide (C), octadeca-6,9-dien-15olide (D), octadeca-9,11-dien-13-olide (E), and octadeca-9,11,15-trien-13-olide (F).

in both spectra, is actually K+2 (CnH2nSCH3) occurring together with the very small ion K (CnH2n−2SCH3). Its presence indicates that probably other mechanisms than a McLafferty rearrangement determine the mass spectrum, as its occurrence requires transfer of hydrogen from the radical to the ion after α-cleavage, as indicated in Scheme 8. Ion L (CnH2n−2OSCH3) now appears at m/z 271. Its formation can be rationalized by cleavage next to the carbonyl group and again H-transfer (Scheme 8). Both ions K+2 and L lose formally methanethiol and three H atoms (51 amu) to form the ions M and J. The two different ion series are isobaric. Therefore, the small ion I is of diagnostic value to locate the oxygen-containing ion. Although obviously the location of double bonds can be determined at least in nonsubstituted macrolides, branching changes the situation. The two macrolides 9-octadecen-13-olide (Figure 11B) and 9-octadecen-11olide (Figure 11C) show completely different mass spectra. While 9-octadecen-13-olide shows a K+2 base peak, accompanied by an intense K-1 ion, they are absent in the respective 11-olide, although the double bond location is identical. The ions J and M dominate in the latter spectrum. Other ions discussed occur but often with more or less hydrogens. The differences might be induced because of the close proximity of

Scheme 7. Formation of Ion H

instrument. The spectrum of tetracos-15-en-24-olide obtained with a quadrupole mass spectrometer differs in the intensities of the ions (Figure 11A). Similarly, m/z 122 occurs together with a small m/z 171, while I is now found at m/z 287 with very low intensity, together with J at m/z 220. The ion m/z 173, present 2579



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Figure 10. Mass spectra of 4,8-dimethyl-3,8-decadien-10-olide (suspensolide, A), 4,8-dimethyl-4,8-decadien-10-olide (ferrulactone, B), 3,7,11-trimethyldodeca-2,6,10-trien-12-olide (niaviolide, C), and 4,8,12-trimethylpentadeca-4,8,12-trien-15-olide (brassicalactone, D).

the thiomethyl groups to the carboxy group in 9-octadecen-11olide. Spectrum 10B is very similar to that of the DMDS adduct of 9-tetradecen-13-olide (Figure 11E), with K+2 and K-1 predominant. In contrast, both the DMDS adducts of 5tetradecen-13-olide (Figure 11D) and 5-tridecen-12-olide (Figure 11F) are dominated by K+2 and I-1. Currently, it seems that no reliable interpretation of mass spectra of DMDS adducts of unsaturated macrolides is possible, except for unsubstituted macrolides. • DMDS adducts can give additional information, but a general fragmentation model is missing.

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CONCLUSIONS The analysis of the mass spectra of a wide variety of macrolides varying in ring-size from 10 to 24, including different alkyl substitution patterns and number of double bonds, allowed the

Figure 11. Mass spectra of the DMDS adducts of 15-tetracosen-24olide (A), 9-octadecen-13-olide (B), 9-octadecen-11-olide (C), 5tetradecen-13-olide (D), 9-tetradecen-13-olide, and 5-tridecen-12olide (F). 2580



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Scheme 8. Mass Spectrometric Fragmentation of DMDS Adducts of Macrocyclic Lactones Exemplified by the DMDS Adduct of 13-Docosen-22-olide

Review

AUTHOR INFORMATION

Corresponding Author

*Tel: +495313917353. Fax: +495313915272. E-mail: stefan. [email protected]. ORCID

Stefan Schulz: 0000-0002-4810-324X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Dr. Jan Bello for helpful comments on the manuscript and the Deutsche Forschungsgemeinschaft for research grant SCHU 984/10-1.

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formulation of rule set for fragmentation. These rules are presented here together with some additions explained during the previous discussion. The following guidelines are useful in the identification of aliphatic macrolides: • A macrolide can be identified by the characteristic ions A (m/z 60, 73, and M-60) and B (M-18, M-36). In some cases, careful differentiation from the spectra of related free fatty acids is necessary. In many spectra, M-28 or M29 ions can also be found. • The ring size and the terminal substituent can be determined in saturated macrolactones by the ions C and E, while in unsaturated macrolides only ion C occurs. The ring size depends also on the substituents in the ring. • The presence and position of methyl groups located between C-2 and C-6 of the chain can be deduced by analyzing ions A and F in saturated macrolides. • The position of a double bond in monounsaturated macrolides can be deduced by ions G, provided the double bond is located not closer than C-4 to the carbonyl group and not in an allyl- or homoallyl-position relative to the terminal C−O bond. • The terminal substituent in polyunsaturated macrolides can be deduced by ion H if it is H, methyl, or ethyl. • DMDS adducts can give additional information, but a general fragmentation model is missing. In our group, these rules have been applied in numerous studies on macrolides, identifying such macrolides in amphibia, beetles, hymenoptera, butterflies, or bacteria.1,3,10−15,19,25,30−35 Nevertheless, it has to be pointed out that complete structure elucidation based on MS alone is rarely possible. Additional information like gas chromatographic retention indices or IR spectroscopy gives valuable input if pure material for NMR analysis cannot be obtained. Final proof usually needs reference material, obtainable, for example, by synthesis.

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REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.7b00366. Information on mass spectrometers and structures of the compounds discussed (PDF) 2581



Review

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Mass Spectrometry of Aliphatic Macrolides, Important Semiochemicals

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