Elucidation of electron ionization mass spectrometric fragmentation pathways of trimethylsilyl ether derivatives of vicinal diols deriving from haplamine by collision-induced dissociation

Research Article

Received: 19 December 2013 Revised: 19 February 2014 Accepted: 21 February 2014 Published online in Wiley Online Library

Rapid Commun. Mass Spectrom. 2014, 28, 1004–1010

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Elucidation of electron ionizationmass spectrometric fragmentationpathways of trimethylsilyl ether derivatives of vicinal diols derivingfromhaplamineby collision-induceddissociationgas chromatography/tandem mass spectrometry and 18O labelling

Sompheary Ea1, Claude Aubert1, Jean-François Rontani2*, Yannick Teral3 andMylène Campredon3

1Laboratoire de Pharmacocinétique et Toxicocinétique (EA 3286), Faculté de Pharmacie, 13385 Marseille, France2Aix-Marseille Université, Mediterranean Institute of Oceanography (MIO), 13288Marseille, Cedex 9; Université du Sud Toulon-Var,83957, CNRS-INSU/IRD UM 110, France3Aix-Marseille Université, Centrale Marseille, CNRS, ISM2-UMR 7313, 13397 Marseille, France

RATIONALE: Formation of vicinal diols was observed after in vitro and in vivo studies of the natural product haplamine(9-methoxy-2,2-dimethyl-2,6-dihydropyrano[3,2-c]quinolin-5-one). These compounds, identified as trans- and cis-3,4-dihydroxy-9-methoxy-2,2-dimethyl-2,3,4,6-tetrahydropyrano[3,2-c]quinolin-5-ones and trans- and cis-3,4,9-trihydroxy-2,2-dimethyl-2,3,4,6-tetrahydropyrano[3,2-c]quinolin-5-ones, have a potential interest in oncology. It is therefore essential toelucidate their electron ionization mass spectrometric (EIMS) fragmentation pathways.METHODS: EIMS fragmentation pathways of trimethylsilyl (TMS) derivatives of 3,4-dihydroxy- and 3,4,9-trihydroxyhaplamines were investigated. These pathways have been substantiated by: (i) comparison with EI massspectra of structural homologues (silylated diols obtained from various chromenes and 1,2-dihydronaphthalene),(ii) low-energy collision-induced dissociation (CID) gas chromatography/tandem mass spectrometry (GC/MS/MS)and (iii) 18O labelling.RESULTS: CID-MS/MS analyses and 18O labelling demonstrated that EI mass spectral fragmentation of these TMSderivatives involves a transannular cleavage of the pyran ring with formation of a characteristic intense cyclicion. The study of the mass spectra of TMS derivatives of different chromenes and 1,2-dihydroxynaphthaleneallowed to confirm the proposed fragmentation pathways and to show that they act only when the pyran ringis present.CONCLUSIONS: Elimination of the neutral element [(CH3)2=C(H)OSi(CH3)3] and formation of cyclic ions play a key roleduring EI mass spectral fragmentation of the TMS derivatives of 3,4-dihydroxy- and 3,4,9-trihydroxyhaplamines. Thesefragmentation pathways could be generalized to TMS derivatives of cyclic compounds possessing vicinal diols close to apyran ring. Copyright © 2014 John Wiley & Sons, Ltd.

(wileyonlinelibrary.com) DOI: 10.1002/rcm.6879

Chemical derivatization has played an important role in gaschromatography/mass spectrometry (GC/MS) for the studyof polar compounds.[1,2] Silylation is by far the majorderivatization procedure for GC/MS analysis.[3–5] Electronionization (EI) mass spectra of various trimethylsilyl (TMS)derivatives have been studied extensively for structuraldeduction[6] and typical rearrangements and migrations oftrimethylsilyl groups were often observed.[7–12]

Recently, we observed the formation of vicinal diols afterin vitro and in vivo studies[13,14] of the natural producthaplamine (9-methoxy-2,2-dimethyl-2,6-dihydro-pyrano[3,2-c]-

* Correspondence to: J.-F. Rontani, Aix-Marseille Université,Mediterranean Institute of Oceanography (MIO), 13288,Marseille, Cedex 9; Université du Sud Toulon-Var, 83957,CNRS-INSU/IRD UM 110, France.E-mail: [email protected]

Rapid Commun. Mass Spectrom. 2014, 28, 1004–1010

quinolin-5-one).[15] These haplamine metabolites, identified astrans- and cis-3,4-dihydroxy-9-methoxy-2,2-dimethyl-2,3,4,6-tetrahydropyrano[3,2-c]quinolin-5-ones (trans- and cis-3,4-dihydroxyhaplamines) (1 and 2) and trans- and cis-3,4,9-trihydroxy-2,2-dimethyl-2,3,4,6-tetrahydropyrano[3,2-c]-quinolin-5-ones (trans- and cis-3,4,9-trihydroxyhaplamines)(3 and 4), could be useful in oncology. Indeed, in vitrostudies show a notable activity on various cancer celllines.[16,17] It may be noted that other similar alkaloidsare also metabolized via dihydroxylated derivatives;thus, a good knowledge of the ions formed during EIMSfragmentation of such compounds seems necessary. In EImass spectra of these silylated diols, we observedintense peaks resulting probably from a transannularcleavage of the pyran ring with the formation of a cyclicion. This characteristic ion has a real interest forsensitive analysis by GC/MS starting from differentcomplex biological matrices.

Copyright © 2014 John Wiley & Sons, Ltd.

Elucidation of EIMS fragmentation of haplamine diol TMS derivatives

In the present work, we thus examined EI mass spectra ofTMS derivatives of the trans- and cis-3,4-diols deriving fromhaplamine. The mass spectra were also compared withthose of the silylated diols obtained from variouschromenes and 1,2-dihydronaphthalene. The formation ofsome characteristic ions was substantiated by low-energycollision-induced dissociation tandem mass spectrometry(CID-MS/MS) and by analysis of synthesized trans-3,4-(18O)-dihydroxyhaplamine.

Figure 1. Total ion chromatogram of a mixture of trans- andcis-3,4-dihydroxyhaplamine (1 and 2) tris-trimethylsilylderivatives.

Figure 2. EI mass spectra of trans- (1) (A), cis-3,4-dihydroxy-haplamine (2) (B), and trans-3,4-(18O)-dihydroxyhaplamine (8)(C) tris-trimethylsilyl derivatives.

Copyright © 2014Rapid Commun. Mass Spectrom. 2014, 28, 1004–1010

EXPERIMENTAL

Chemicals

Haplamine was extracted from Haplophyllum perforatum Kar.and Kir. at the Institute of Plant Substances (Tashkent,Uzbekistan) according to the procedure cited.[18] Pure standardsof chromenes were obtained from the Laboratoire ISM2(Luminy, France). The 1,2-dihydronaphthalene was pur-chased from Aldrich (St. Quentin Fallavier, France). 3-meta-Chloroperbenzoic acid (MCPBA) was purchased from SigmaAldrich (St. Quentin Fallavier, France). Bis(trimethylsilyl)trifluoroacetamide (BSTFA) was obtained from Interchim(Montluçon, France).

Preparation of 3,4-dihydroxy derivatives

trans- and cis-3,4-Dihydroxyhaplamines (1 and 2), 3,3-dimethyl-2,3-dihydro-1H-benzo[f]chromene-1,2-diol (5), 3-methyl-3-phenyl-2,3-dihydro-1H-benzo[f]chromene-1,2-diol(6) and 2,3,4-tetrahydronaphthalene-1,2-diol (7) were preparedusing respectively haplamine, 3,3-dimethyl-3H-benzo[f]-chromene, 3-methyl-3-phenyl-3H-benzo[f]chromene) and1,2-dihydronaphthalene.

Formation of trans/cis-diols

These starting compounds (6 mg) were added to a solution ofMCPBA (12 mg) in dichloromethane (4 mL) previously driedover anhydrous Na2SO4 and incubated for 120 min at roomtemperature. The reaction mixture was washed three timeswith NaHCO3 solution (10 % in water) (5 mL) and the organicphase (dichloromethane) was then dried over anhydrousNa2SO4, filtered and concentrated.[19] Hydrolysis of the resultingepoxides was subsequently carried out in 200 μL H2O or H2

18O

Figure 3. EI mass spectrum of trans- (3) (A) and cis-3,4,9-trihydroxyhaplamine (4) (B) tetra-trimethylsilyl derivatives.

wileyonlinelibrary.com/journal/rcmJohn Wiley & Sons, Ltd.

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with 5 μL concentrated H2SO4 under reflux for 1 h at 90–95°C.After cooling, the mixture was extracted with dichloromethane(5 mL). The dichloromethane extract was dried over anhydrousNa2SO4, filtered and concentrated (95-85% purity checked byGC). It may be noted that in the case of hydrolysis with H2

18O,the labeling took place preferentially at the position 4, due tothe formation of the more stable carbocation (allylic carbocation)during the opening of the epoxide.

Formation of TMS derivatives

Compounds (5–20 μg) to be silylated were taken up in200 μL of a mixture of anhydrous ethyl acetate and BSTFA(1:1; v/v) and allowed to react at 80°C for 1 h. After dilution

Scheme 1. Proposed formation of common ionstrihydroxyhaplamine (3 and 4) and chromenediol (5

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with 100 or 200 μL ethyl acetate the mixture was analyzedby gas chromatography/electron impact mass spectrometry(GC/EIMS).

Gas chromatography/electron impact tandem massspectrometry

GC/EIMS and GC-EIMS/MS experiments were performedusing anAgilent 7000A tandem quadrupole gas chromatographsystem. A cross-linked 5% phenyl-methylpolysiloxane capillarycolumn (HP-5MS; 30 m × 0.25 mm, 0.25 μm film thickness;Agilent) was employed. Analyses were performed with aninjector operating in splitless mode (with 0.5 min splitlessperiod) set at 270 °C and the oven temperature programmed

of 3,4-dihydroxyhaplamine (1, 2 and 8), 3,4,9-and 6) trimethylsilyl derivatives.

y & Sons, Ltd. Rapid Commun. Mass Spectrom. 2014, 28, 1004–1010


from 70 °C to 130 °C at 20 °Cmin�1, then to 250 °C at 5 °Cmin�1

and then to 300 °C at 3 °C min�1. The following massspectrometric conditions were employed: electron energy, 70 eV;source temperature, 230 °C; quadrupole 1 temperature, 150°C;quadrupole 2 temperature, 150°C; collision gas (N2) flow,1.5 mLmin�1; quench gas (He) flow, 2.25 mLmin�1; mass range,50–520 amu; cycle time, 313ms. The use of CIDwas optimized bycollision voltages adjusted at 5, 10, 15, 20, 25 and 35 eV.Under these experimental conditions, for example, the total

ion chromatogram presented in Fig. 1 shows an excellentseparation for the mixture of TMS derivatives of trans- andcis-3,4-dihydroxyhaplamines (1 and 2).

RESULTS AND DISCUSSION

Electron ionisation (EI) mass spectra of the trimethylsilyl(TMS) derivatives of trans- and cis-3,4-hydroxyhaplamines(1 and 2) are reported in Figs. 2(A) and 2(B). These mass

Figure 4. EI mass spectra of trans-dihydroxychromenes (5)(A) and (6) (B) bis-trimethylsilyl derivatives.

Figure 5. EI mass spectrum of 1,2-dihydroxynaphthalene (7)bis-trimethylsilyl derivative.


spectra, which are dominated by a fragment ion at m/z 348,exhibited a very weak molecular ion at m/z 507 and fragmentions at m/z 492 [M – 15]+ and m/z 418 [M – OSi(CH3)3]

+.

classically observed in EI mass spectra of silylatedcompounds. trans (Fig. 2(A)) and cis (Fig. 2(B)) isomersshowed very similar mass spectra (with only minor

Scheme 2. Proposed formation of specific ions of 3,4-dihydroxy-haplamine (1, 2 and 8) and 3,4,9-trihydroxyhaplamine(3 and 4) trimethylsilyl derivatives.


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differences in the intensity of several ions). The TMSderivatives of trans- and cis-3,4,9-trihydroxyhaplamines(3 and 4) (Figs. 3(A) and 3(B)) showed mass spectra verysimilar to those of the compounds 1 and 2. Owing to the9-O-desmethylation of 3,4-dihydroxyhaplamines, the differentfragment ions were shifted by 58 mass units in EI massspectra of the TMS derivatives of compounds 3 and 4. Forexample, the molecular ion at m/z 507 and the base peak atm/z 348 were shifted to m/z 565 and 406, respectively (Figs. 3(A)and 3(B)).In order to explain the formation of the abundant fragment

ions atm/z 348 (for compounds 1 and 2) or 406 (for compounds3 and 4), we proposed the mechanisms described in Scheme 1(pathway I). These mechanisms involve initial classical loss ofa methyl radical (ion a+) by the ionized TMS group carried bythe carbon 4 and subsequent cyclization between the resultingcarbocation and the oxygen of the pyran ring affording thecyclic ion b+. Heterolytic cleavage of the pyran ring then affordsthe final cyclic ion c+ atm/z 348 (for compounds 1 and 2) or 406(for compounds 3 and 4) and the neutral element [(CH3)2C=C(H)OSi(CH3)3]. This pathway is well supported by thepresence of a peak at m/z 229 in EI mass spectra of 3,4-dihydroxychromenes (5 and 6) (Figs. 4(A) and 4(B)). Indeed,the loss of [(CH3)2C=C(H)OSi(CH3)3] and [CH3(Ph)C=C(H)OSi(CH3)3] observed for compounds 5 and 6, respectively,is in good agreement with such a mechanism. It is veryinteresting to note that the TMS derivative of 1,2-dihydroxynaphthalene (7) exhibits a completely different EImass spectrum (Fig. 5). The typical ion c+ previouslydescribed is not observed in this case. This confirms that theproposed mechanism is only possible in the presence ofthe oxygen of the pyran ring. The ion c+ may also resultfrom the loss of a methyl radical by the ion d+. at m/z 363(for compounds 1 and 2; Figs. 2(A) and 2(B)), 365(for compound 8; Fig. 2(C)), 421 (for compounds 3 and 4; Fig. 3)

Table 1. Product ion scan (CID-MS/MS) of the precursor ionsobtained from TMS derivatives of unlabelled (1) and labelled (815 eV

Precurso

m/z 507 m/z 509 m/z 492

Product ions(m/z) (%)a

Product ions(m/z) (%)


73 6 73 4 73 39144 3 144 1 147 19320 47 320 61 348 100334 28 334 32 402 29348 100 350* 100 476 6363 3 365* 11 492 21402 28 402 18418 64 418 30464 6 466* 6492 51 494* 52507 2 509* 2aRelative abundance.*Labelled ions


and 244 (for compounds 5 and 6; Fig. 4) obtained after classicalhomolytic cleavage between the two adjacent TMS ether groupsand loss of the neutral element [CH3(R)C=C(H)OSi(CH3)3](Scheme 1, pathway II).

Classical α-cleavage between the two trimethylsilyloxygroups affords the fragment ion e+. after opening of thepyran ring (Scheme 1, pathway III). Homolytic cleavageyields a neutral cyclic molecule and the ion f+. at m/z 144(for compounds 1, 2, 8, 3, 4 and 5; Figs. 2(A), 2(B), 2(C), 3(A),3(B), 4(A)) or m/z 206 (for compound 6; Fig. 4(B)). Theformation of ion h+ at m/z 364 (for compounds 1 and 2;Figs. 2(A) and 2(B)), 422 (for compounds 3 and 4; Fig. 3), 245(for compounds 5 and 6; Fig. 4) and 366 (for compound 8;Fig. 2(C)) is proposed in Scheme 1 (pathway IV). Thispathway involves an initial hydrogen transfer between amethyl group of the carbon 2 and the ionized oxygen of thepyran ring. Opening of the pyran ring of the resulting distonicion g+. and cyclization gives then the ion h+ and the radicalfragment [CH2=C(R)–C

•(H)OSi(CH3)3] stabilized byconjugation. For the formation of the fragment ion j+,exclusively observed with 3,4-diols deriving from haplamine,at m/z 334 (for compound 1, 2 and 8; Fig. 2) or m/z 392 (forcompounds 3 and 4; Fig. 3), we propose a pathway involvinginitial transfer of the TMS group from the TMS ether group ofthe carbon 4 to the oxygen of the ionized carbonyl group(Scheme 2). Cleavage of the pyran ring of the distonic ion i+.

thus formed then affords the ion j+.These proposed fragmentation pathways are well

supported by the fragment ions obtained by CID (Table 1).These results, for example, allowed confirmation that theabundant ion c+ at m/z 348 is formed starting from boththe ions a+ and d+. at m/z 492 and 363, respectively. Theinvolvement of such a pathway was also substantiated by18O labelling. The shift of the ions c+ and d+. to m/z 350 and365, respectively, in EIMS of the TMS derivative of trans-3,4-

at m/z 507 (a), 509 (a), 492 (a), 494 (a), 363 (b) and 365 (b)) trans-dihydroxyhaplamine. Collision energy: (a) 20 eV; (b)

r ion

m/z 494 m/z 363 m/z 365




73 12 73 12 73 13147 10 272 4 272 3350* 100 304 3402 21 320 13 320 6478* 4 334 6 334 10494* 25 348 100 350* 100

363 8 365* 9



(18O)-dihydroxyhaplamine (8) (Fig. 2(C)) and the resultsobtained after CID of labelled precursor ions at m/z 509, 494and 365 (Table 1) well support the proposed pathways I andII (Scheme 1). The lack of shift of the ion j+ at m/z 334 is alsoconsistent with the mechanism proposed in Scheme 2.The formation of the well-known fragment ion at m/z 147

characteristic of polysilylated compounds was observed forevery compound studied. This ion is formed after loss of amethyl radical from one silyl group and subsequentrearrangement.[20]

EI mass spectra of the TMS derivatives of dihydroxy-chromenes 5 and 6 (Fig. 4) exhibit a specific peak at m/z 317.For the formation of the fragment ion at m/z 317, we proposea pathway involving initial transfer of the TMS group fromthe TMS ether group in position 3 to the oxygen of the pyranring (Scheme 3). Heterolytic cleavage of the resulting distonicion k+. yields the disilylated cyclic ion l+ (m/z 317) and theradical [CH3(R)C=C(H)O•] well stabilized by conjugation.The EI mass spectrum of the TMS derivative of 1,2-

dihydroxynaphthalene (7) reported in Fig. 5 exhibitsfragment ions completely different to those observed in EImass spectra of the various compounds previously studied.The formation of the intense fragment ion m+. at m/z 218

Scheme 4. Proposed fragmentation of 2,3,4-tetrahydro-naphthalene-1,2-diol bis(trimethylsilyl) derivative (7).

Scheme 3. Proposed formation of specific ions of chromenediolbis(trimethylsilyl) derivatives (5 and 6).


was attributed to classical elimination of a neutral moleculeof trimethylsilanol. Classical α-cleavage between thetrimethylsilyl ether groups with opening of the cyclohexanering yields the distonic ion n+., whose the cleavage affordsthe radical cation o+. at m/z 192 and the neutral element[CH2=C(H)OSi(CH3)3]. Finally, the loss of a methyl radicalby the TMS group of the ion o+. gives the ion p+ at m/z 177(Scheme 4).

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CONCLUSIONS

Elimination of the neutral element [(CH3)2=C(H)OSi(CH3)3]and formation of cyclic ions play a key role during EI massspectral fragmentation of the TMS derivatives of 3,4-dihydroxy- (1, 2) and 3,4,9-trihydroxyhaplamines (3, 4)affording characteristic and intense ions at m/z 348 and 406,respectively. Some fragmentation pathways were proposedin order to explain the formation of these ions. The genesisof the characteristic ions was confirmed by CID-MS/MSand 18O labelling.

The study of the mass spectra of TMS derivatives ofdifferent chromenes and 1,2-dihydroxynaphthalene allowedto confirm the proposed fragmentation pathways and toshow that they act only when the pyran ring is present. Thesepathways could thus be generalized to TMS derivatives ofcyclic compounds possessing vicinal diols close to a pyran


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ring. It is interesting to note that the formation of several otherions at m/z 334 (1 and 2), 392 (3 and 4) and 317 (5 and 6) seemsto involve trimethylsilyl transfers. Such migrations arecommon upon electron ionization and have often beenobserved previously.[7–12] In conclusion, we can reaffirm thatthe combination of a GC/EIMS/MS system and isotopiclabelling constitutes an excellent tool to elucidate novelfragmentation routes.

AcknowledgementsThanks are due to two anonymous referees for their usefuland constructive comments.

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Elucidation of electron ionization mass spectrometric fragmentation pathways of trimethylsilyl ether derivatives of vicinal diols deriving from haplamine by collision-induced dissociation