Differentiation of the diastereomeric synthetic precursors of isofebrifugine and febrifugine by electrospray ionization tandem mass spectrometry

Abstract

Febrifugine is an alkaloid with potent antimalarial activity isolated from Dichroa febrifuga and Hydrangea umbellate, and it exists naturally with its diastereomeric component, isofebrifugine. Here we report the differentiation of diastereomeric synthetic precursors of isofebrifugine (1, cis) and febrifugine (2, trans) and a structurally similar model diastereomeric pair without a halogen substituent (3 and 4) by electrospray ionization (ESI) tandem mass spectrometry. Compounds 1-4 contain a tert-butoxycarbonyl (BOC) substituent, and the collision-induced dissociation (CID) spectra of the [M+H](+), [M+Na](+) and [M+Li](+) ions of 1-4 include the expected product ions corresponding to the loss of C(4)H(8) (isobutene) and of C(5)H(8)O(2) (BOC-H). Loss of C(5)H(8)O(2) is dominant in cis isomers (1 and 3) and/or loss of C(4)H(8) ions is dominant in trans isomers (2 and 4). The decomposition of [M+H](+) ions shows stereoselectivity in the formation of the [M+H-(BOC-H)-C(3)H(5)OBr](+) and [M+H-(BOC-H)-C(6)H(5)CH(2)OH](+) ions. The [M+Cat](+) ions (where Cat = Na or Li) additionally show loss of NaBr and HBr from [M+Cat-(BOC-H)](+), and these product ions are constantly more abundant in cis isomers than in trans isomers. The stereoselectivity for the product ion corresponding to the loss of [(BOC-H)+C(3)H(5)OBr] from [M+H](+) ions differs from that from [M+Cat](+) ions.

Stereochemical effects in fragmentation of diastereoisomers of protected diethyl 1,2-diamino-alkylphosphonates

“…In some cases, differences in the abundances or formation of specific fragment ions can be observed in mass spectra especially when electron ionization (EI) has been applied as an ionization technique. Soft ionization techniques (chemical ionization (CI), fast atom bombardment (FAB), liquid secondary ion mass spectrometry (LSI) or electrospray (ESI)) give abundant protonated or cationized molecules from which stereochemical information can be obtained by collision‐induced dissociation (CID) 3–5. Investigation of fragmentation stereochemistry can be useful for better understanding of the factors influencing differences in the fragmentation of diastereoisomers of new compounds.…”

Mass Spectrometry in India

“…As a continuation of this work, Prabhakar et al at IICT addressed the differentiation of diastereomers of biological or synthetic importance, such as hydroxy brevicomins, conduramine derivatives, precursors of febrifugene/ isofebrifugene and a-sulfanyl b-amino acid derivatives. [93][94][95][96][97] A few sets of structural isomers, substituted diaryl ethers and benzoxazolinones, were also differentiated. 98,99 Prabhakar and colleagues demonstrated the occurrence of EI-induced Claisen rearrangements and Newman-Kwart rearrangements with the aid of high-resolution mass spectrometry (HRMS) and MS/MS.…”

Rapid differentiation of nucleotide phosphoramidate diastereomers by electrospray ionization tandem mass spectrometry

“…Although mass spectrometry traditionally has not been widely recognized as a technique for characterizing stereoisomers, numerous reports have demonstrated the application of mass spectrometry to differentiate diastereomers based on the stereospecific fragmentation behavior of diastereomeric compounds. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] However, there has not been a systematic study on nucleotide phosphoramidate diastereomers using mass spectrometry.…”

“…The challenge for the characterization of stereoisomers by mass spectrometry is that isomeric molecules have the identical mass‐to‐charge ratio, and therefore, they cannot be distinguished. Although mass spectrometry traditionally has not been widely recognized as a technique for characterizing stereoisomers, numerous reports have demonstrated the application of mass spectrometry to differentiate diastereomers based on the stereospecific fragmentation behavior of diastereomeric compounds . However, there has not been a systematic study on nucleotide phosphoramidate diastereomers using mass spectrometry.…”