Study Of Natural Product By Density Functional Theory And Vibrational Optical Activity

There is a strong connection between the absolute configuration(AC)and conformational population of drug molecule and the characters of pharmaceutical,which is aimed at depicting the stereostructure of chiral drug molecules in chemistry.The difference of stereostructure of chiral drug molecules makes the properties and pharmacology of drug different,affecting the way to use medicine and to treat diseases.Chemical synthesis,Mosher ester analysis,X-ray crystallography and chiral spectroscopy are usually employed to obtain the AC and conformations,among which chiral spectroscopy is the simplest,the most economic and effective method.In current research,Fourier transfer infrared(FTIR),Vibrational circular dichroism(VCD)and Raman optical activity(ROA)were employed to detect experimental IR-VCD and Raman-ROA spectra.The conformations and absolute configuration of chiral molecules were showed up,combined with the comparison to corresponding simulated IR-VCD and Raman-ROA spectra,calculated within density functional theory(DFT).In this paper,It presents the conformations and configurations of such natural chiral molecule as Gastrodin,Oleanolic acid,Sophocarpidin and Rutin through the analysis of calculated and experimental spectra.(1)Gastrodin owns the β-D-glucopynose ring and phenylcarbinol radical.The level B3LYP/6-311++g(d,p)and B3LYP/cc-p VTZ were employed to do the conformational search on flexible binds in such groups as hydroxy,-CH2 OH and-C1-O-C1’.After obtaining conformations,the optimization and the calculation on IR-VCD and Raman-ROA spectra were performed,respectively using B3LYP/6-311++g(d,p)and B3LYP/aug(sp)-cc-p VDZ in gas phase,polarized continuum model(PCM)and explitic+PCM model within density functional theory(DFT).In the meantime,the IR-VCD and Raman-ROA spectra were measured in film,DMSO-d6 and water.Finally,the AC and conformational population of Gastrodin were confirmed by the comparison of the experimental and simulated IR-VCD and Raman-ROA spectra.It turns out that Gastrodin owns 4C1 chair configuration for sugar ring and 5 chiral carbon center with 1S 2R 3S 4S 5R,of which peripheral hydroxyl groups adopt equatorial configuration.Gastrodin shows up 14 conformations in room temperature,among which tttt G+g-U,tttt G+g-D,tttt G-g+U and tttt G-g+D are main conformations,being 24.7%,9.7%,30.1% and 9.2%,respectively.The angle of the plane of sugar ring and benzene ring is fixed by 16° roughly among conformations.The signals in IR and VCD spectra are red-shifted because of inter-and intramolecular hydrogen-bonding.(2)The Oleanolic acid is the triterpene compound with five rings which include 4 cyclohexane and 1 cyclohexene.The conformational search on the connection between rings and the direction of hydroxyl and carboxyl on Oleanolic acid were performed in B3LYP/6-311++g(d,p)level.After getting conformations,the optimization and the calculation of IR-VCD and Raman-ROA spectra were gone on using B3LYP/6-311++g(d,p)and B3LYP/aug(sp)-cc-p VDZ level.Meanwhile,the information of Oleanolic acid were registered in the IR-VCD and Raman-ROA spectra by means of the VCD and Raman chiroptical tool.Finely,the AC and conformational population of Oleanolic acid were obtained by the comparison between simulated and measured IR-VCD and Raman-ROA spectra.It turns out that Oleanolic acid has 8 chiral carbon center with 2S 7S 12 R 13R 16 S 18R 21 R 22S and A/B/D/E ring with trans configuration as well as C ring with half-chair configuration.At room temperature,Oleanolic acid owns 6 conformations whose Boltzmann population are 14.4%,18.6%,22.8%,11.6%,14.7% and 17.8%,respectively.(3)Sophocarpidin consist of two quinolinidine ring,having four 6-members ring.The conformational search on the connection of A/B,C/D,A/C and B/C were performed with the level B3LYP/6-311++g(d,p)and B3LYP/cc-p VTZ.The optimization and the spectra of IR-VCD and Raman-ROA of Sophocarpidin were obtained,optimized in B3LYP/6-311++g(d,p),calculated at B3LYP/6-311++g(d,p),B3LYP/cc-p VTZ and B3LYP/aug(sp)-cc-p VDZ in PCM.Meanwhile,the experimental IR-VCD and Raman-ROA spectra were measured in film.Finally,the AC and conformational population were confirmed by the comparison of calculated and measured IR-VCD and Raman-ROA spectra.It turns out that Sophocarpidin owns two conformations at room temperature and 6 chiral centers,named A/B-trans C/D-trans and A/B-trans C/D-cis whose Boltzmann population are 60% and 40% roughly,including 4 chiral carbon centers with 5S 6S 7R 11 R and two nitrogen centers marked as N-1 and N-16,being R chirality in A/B-trans and R(S)chirality in C/D-trans(C/D-cis),respectively.The configuration of each of ring of Sophocarpidin is A-chair,B-chair,C-chair and D-sofa.The connection of A/C ring and B/C ring in two conformations of Sophocarpidin all adopts A/C-cis and B/Ccis.(4)The Rutin consist of flavone,β-D-glucopynose and D-mannose,having the strong flexible bond to get more conformations.The conformational search of Rutin were performed on each of flexible bonds at B3LYP/6-311++g(d,p)level,and then the conformation obtained in conformational search were optimized and calculated for IR-VCD spectra at B3LYP/6-311++g(d,p)level in gas phase.Meanwhile,the observed IR-VCD spectra were measured in film.The AC and conformational population of Rutin were confirmed by the comparison between calculated and observed IR-VCD spectra.It turns out that Rutin has 5 rings,among which A/B/C ring adopt plane configuration,D ring adopts 4C1 chair configuration and E ring adopts 4C1 chair configuration.The angle of plane between C ring and A/B ring is 35° or so in all conformations of Rutin.At room temperature,Rutin has 24 conformations,among which 9 main conformations and the rest conformations take up 71.5% and 28.5%,respectively.Meanwhile,there are lots of intramolecular hydrogen-bonding because of the large number of proton donators and proton acceptor.