Lecture 3 - Department of Chemistry
Lecture 3 - Department of Chemistry
Lecture 3 - Department of Chemistry
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Elucidation <strong>of</strong> the Structure and Biological Activity <strong>of</strong>a New Sesquiterpene from Cistus creticus L.Konstantinos Hatzellis, Georgia Pagona, Apostolos Spyros,Costas Demetzos, Haralambos E. Katerinopoulos†<strong>Department</strong> <strong>of</strong> <strong>Chemistry</strong>, University <strong>of</strong> Crete, Heraklion 71409, Crete,Greece, and School <strong>of</strong> Pharmacy, <strong>Department</strong> <strong>of</strong> PharmaceuticalTechnology, Panepistimiopolis Zografou 15771, University <strong>of</strong> Athens,Athens, Greece.9134 53 4a 6A B2 8a 71 81112H10
Composition <strong>of</strong> the Essential Oil from the Resin <strong>of</strong> C. creticus L.ComponentsRt% στο δείγµαladano3.d011 2-methyl butanoic acid 5.674 0.132 Tricyclene 7.432 0.183 α-Pinene 7.895 2.674 Camphene 8.410 1.395 Thuja-2,4(10)-diene 8.578 0.056 Benzaldehyde 8.684 0.057 β-Pinene 9.463 0.608 Phenol 9.575 0.169 Hexanoic acid 10.200 0.0410 α-Phellandrene 10.565 0.1211 α-Terpinene 11.100 0.1312 p-Cymene 11.420 0.2313 Limonene 11.638 0.3514 γ-Terpinene 12.983 0.2515 Acetophenone 13.182 0.0316 Terpinolene 14.353 0.1917 Linalool 14.881 0.1018 3,5-heptadien-2-one, 6-methyl15.037 0.22(E)-19 [R]-(+)-Norinone 16.550 0.0620 trans-Pinocarveol 16.789 0.9921 Camphor 16.939 0.1622 3-Methylcamphenilol 17.192 0.4723 Isoborneol 17.616 0.1724 Borneol 18.147 2.0725 4-Terpineol 18.653 1.0226 p-Cymen-8-ol 19.093 0.1427 α-Terpineol 19.462 4.5528 Myrtenol 19.728 0.2029 Verbenone 20.094 0.0530 trans-Carveol 20.636 0.1331 1-Cyclohexene-1-carboxaldehyde, 4-(1-methylethyl)-23.174 0.0532 Bornyl acetate 23.778 0.1033 Thymol 24.092 0.0334 Carvacrol 24.577 1.0335 Megastigmatrienenone 26.445 0.0736 α-Cubebene 26.821 0.1037 Longicyclene 26.933 0.0638 Copaene 28.054 0.6439 β-Boutbonene 28.435 0.14ComponentsRt% στο δείγµαladano3.d0140 2-butanone,4-(2,2-dimethyl-6-methylenecyclo hecyl-)28.892 0.1241 Eugenol methyl ether 29.152 0.0542 Isocaryohryllene 29.421 0.0743 β-Caryophyllene 30.033 1.1044 α-Guaiene 30.827 0.1345 β-Cubebene 31.328 0.1246 α-Caryophyllene 31.488 0.1247 Arromadendrene 31.826 0.4548 Drimane Sesquiterpene 32.634 18.5949 Eremophilene 33.108 2.4150 Ledene 33.420 1.1151 α-Muurolene 33.539 0.2452 1,1,4α-trimethyl-5,6-dimethylenedecahydronaphthalene33.875 0.1053 γ-Cadinene 34.131 0.2954 δ-Cadinene 34.544 1.7155 Cubenene 34.910 0.5956 Cyclohexane,1-methyl-2,4-bis(1-methylethenyl)-(1.alpha,2.beta,4,beta)35.094 0.2357. Palustrol 36.355 0.1458. Iasocaryorhyllene 36.613 0,1559. Caryophyllene Oxide 36.946 0.3660. Epiglobulol 37.432 1.6761. Ledol 37.859 0.8762. Cubenol 38.819 1.1563. β-Selinenol 39.708 0.4864. 7[11]-Selinen-4α-ol 39.898 1.1065. Viridiflorol 40.024 0.6566. Sclareol Oxide (cisA/B) 48.356 0.4267. β-Selinene 51.565 0.7568. Manoyl Oxide 52.401 10.1069. Epimanoyl Oxide 53.262 14.6970. Kaur-16-ene 53.842 0.2171. Manool 54.228 0.1372. Hunulane-16-dien-3-ol 55.287 0.7573. (7α-Isopropenyl-4,5-dimethyloctahydroindene-4-yl)methanol74. 4α-7,7,10αtetramethyldodecahydrobenzolf)chromen-3-ol58.025 0.2759.390 0.3175. 3-Oxomanoyle Oxide 59.895 0.09Total in the mixture 80.56%
Analysis <strong>of</strong> the components <strong>of</strong> Labdanum by Gas ChromatographyMass Spectrum <strong>of</strong> Major Component204
3 4 4a 5 62 8a 71 81213H11cis-drima-7,9(11)-diene910Htrans-drima-7,9(11)-diene
OOOOOOOOO3 4 5OHO23A + 23BOHOHtransπορειαOO OH10 9O7cisπορειαOcisπορεια6H12 + ίχνη 8 8 + ίχνη 12HOSiMe 3OSiMe 3∆ιαχωρισµόςSeparation <strong>of</strong>διαστερεοϊσοµερώνdiastereomersHH14 13OOH18A + 18BH15A + 15BOBrH19A + 19BOBrH16A + 16BOOH20H17H1 2H
18a4aOH5HHOHbeta-equatorial alcohol 9Btrans-attack to alpha facealpha-axial alcohol 9Acis-attack to beta face
OO SiMe 3OH8LDA, Me 3 SiCl0°C, 79%H13TBAF, MeITHF, 90%H15A - 15BPBP, AcOH2.5h, rt, 94%H33OHCH 3 LiTHF/HMPA 7:1-78 o C έως RT24 h47%Burgess reagent(MeO 2 CNSO 2 NEt 3 )Et 3 N, THFreflux, 48hH17OCH 2DBU, toluene3.5h, reflux, 93%HO16A - 16BBrH2 (85%)
Comparing NMR data <strong>of</strong> the cis- and the trans-analogwith those <strong>of</strong> Demedzos et al…13 CNMRC 1 C 2 C3 C 4 C 4a C 5 C 6 C 7 C 8 C 8a C 9 C 10 C 11 C 12 C 13A.F. Barreto et al.trans-product 33.4 42.3 19.1 37.8 37.9 158.3 131.3 126.6 24.4 48.7 101.8 21.2 22.2 33.0 20.6H. Akita et .al.trans-product 33.4 42.2 19.1 37.7 37.8 158.2 131.2 126.5 24.3 48.7 103.7 21.1 22.1 32.9 20.6C. Demetzos et al.37 32.2 22.7 39.6 39.1 146.5 144.5 117.7 29.7 39.8 106.2 21.1 15.7 14.1 21.6H. E.Katerinopoulos et al,cis -product34.2 43.7 18.7 37.5 37.8 150.2 131.7 125.2 32.2 49.8 104.9 21.5 23.6 33.0 20.41 Η NMR H 7 (CH) H 9 (CH 2) H 9’(CH 2) H 10 (CH 3) H 11 (CH 3) H 12 (CH 3) H 13 (CH 3)Polovnika et al.trans-productA.F. Barreto et al.trans-productH. Akita et .al.trans-product5.65 4.77 4.81 1.77 0.90 0.84 0.945.65 4.78 4.83 1.78 0.91 0.85 0.955.65 4.80 4.84 1.80 0.93 0.87 0.97C. Demetzos et al. 5.37 4.64 4.69 1.7 0.85 0.75 1.5H. E. Katerinopoulos et alcis -product5.48 4.93 4.94 1.77 0.83 0.70 1.02
0.9290.8100.7961 H-NMR SPECTRUM3 methyl groups : 1.73ppm (s), 0.92ppm (s),0.79ppm (d, next to tertiary carbon)3 olefinicΗ : 4.70ppm (d) 5.34ppm (bd)1.0991.1251.1511.3961.4041.4201.4471.4341.5021.4551.5271.6631.5561.7391.7721.7971.8441.8721.9111.9381.9792.1532.0112.2023.003.041.221.871.371.052.003.061.100.902.361.431.964.03.02.01.00.04.7104.7012.085.05.3545.3420.96ppm (t1)
15.76120.77329.25921.09231.39213 C-NMR SPECTRUM15 carbon atoms, 4 olefinic150.309146.394117.893108.25138.71537.71632.29331.50739.65339.42915010050ppm (t1)
15.57920.91220.589 DEPT 45 oppm (f1)100DEPT SPECTRA50117.704108.06639.44438.51437.51631.30831.20129.07032.102
DEPT SPECTRA DEPT 90 o : CH117.70438.50537.504ppm (f1)10050
15.58320.59520.920DEPT SPECTRADEPT 135 o : CH 3 & CH positive peaks, CH 2 negative peaks.Peak at 108 ppm: exocyclic double bond !117.704108.06539.45038.52137.52732.10831.31831.20529.54029.077ppm ( t1 )10050
Initial Remarks•Molecular Weight: 204•Molecular Formula: C 15 H 24•Degree <strong>of</strong> Unsaturation: 4•Primary Carbons: 3•Secondary Carbons: 6•Tertiary Carbons: 3•Quaternary Carbons: 3Two double bonds, two rings, isopropenyl group?44a8356218a7911131210
H-H gCOSY SPECTRUM44a8356218a7911131210H1MeH2H8H4MeH8'H7
H-H gCOSY SPECTRUMPositionProtonδ 1 H(ppm)COSY1 H 11.64 (m) H 2,2’,H 1323H 21.49 (m) H 1,H 2’,H 3’H 2’1.39 (m) H 1,H 2,H 3,3’H 31.76 (m) H 3’,H 4’H 3’1.28 (brd, 12.9) H 2,2’,H 3,H 4,4’3564H 41.90 (m) H 3’,H 4’H 4’2.17 (m) H 3,3’,H 4218a79115 H 55.33 (brd, 6.0) H 6,6’6H 61.98 (m) H 5,H 6’,H 7H 6’1.84 (m) H 5,H 6,H 71344a812107 H 72.12 (brd, 13.0) H 6,H 6’,H 8’8H 81.90 (brd, 13.0) H 8’H 8’1.11 (dd,13.0,13.0)H 7,H 810 H 101.72 (s) H 1111 H 114.69 (d,4.5) H 1013 H 130.78 (d,7.0) H 1Τα πρωτόνια που χαρακτηρίζονται’ π.χ. Η-8’, δηλώνουνπρωτόνια ψευδοαξονικής διαµόρφωσης.
C-H gHMQC SPECTRUMCorrelation <strong>of</strong> carbons and protons in each group356218a79111344a81210
General ConclusionsC-H gHMQC SPECTRUMCarbonδ 13 C(ppm)Protonδ 1 HC-1 38.71 H 11.64 (m)C-2 31.40C-3 29.26H 2H 2΄H 3H 3΄1.49 (m)1.39 (m)1.76 (m)1.28 (brd)C-4 32.30 H 4΄2.17 (m)C-5 117.90 H 55.33 (brd)C-6 31.50H 6H 6΄1.98 (m)1.84 (m)C-7 37.71 H 72.12 (brd)C-8 39.65H 8H 8΄1.90 (brd)1.11 (dd)C-10 21.09 H 101.72 (s)C-11 108.26 H 114.69 (d)C-12 20.77 H 120.91 (s)C-13 15.76 H 130.78 (d)
H-H interaction through spaceNOESΥ SPECTRUM44a8356218a7911131210HHMeHHMeH
Conclusions from NOE interactionsMeH2H1H7H 8H4MeH8'‣ The resonance <strong>of</strong> axial Η-8’ appears as a pseudotriplet (doublet <strong>of</strong> doublets) due tothe J coupling with Η-8 και Η-7 ( 2 J 7,8’ = 3 J 8,8’ = 13Hz).‣ These J values correspond to a trans-diaxial conformation for Η-8’ and Η-7, whileit suggests an equatorial conformation for the bulky isopropenyl group that is facingthe same direction with Η-8’.‣ A strong ΝΟΕ observed between Η-12 και Η-13 confirms the proximity <strong>of</strong> the twomethyl groups.‣ Moreover, the proton Η-8’ interacts strongly with the Η-12 a fact indicating that theMe-12 is axial.‣ Finally, axial H-7 interacts strongly with H-1 that must be also axial, confirming thatMe-13 is equatorial.All three groups adopt a syn conformation!
Comparing NMR Spectra values.13 CNMRC 1 C 2 C3 C 4 C 4a C 5 C 6 C 7 C 8 C 8a C 9 C 10 C 11 C 12 C 13H. Itokawa etal. 38.69 31.37 29.23 32.29 146.28 117.85 31.37 37.71 39.67 39.44 150.14 21.04 108.17 20.76 15.75C. Demetzos etal α 39.10 22.70 21.60 32.20 144.50 117.70 29.70 37.00 39.60 39.80 146.50 21.10 106.20 15.70 14.10IsolatedEremophilene38.70 31.40 29.26 32.30 146.39 117.90 31.50 37.71 39.65 39.43 150.29 21.09 108.26 20.77 15.561 Η NMRH. Itokawa et al.H 5 (CH) H 11 (CH 2) H 11’(CH 2) H 10 (CH 3) H 12 (CH 3) H 13 (CH 3)5.37 (m) 4.70 (brs) 1.73 (s) 0.79 (d, 6.0) 0.92 (s)C. Demetzos et al α 5.37 4.64 4.69 1.7 0.85 0.75Isolated Eremophilene5.33 (brd, 6.0) 4.69 (d, 4.5) 1.72 (s) 0.78 (d, 7.0) 0.91 (s).[α] D+12.45 ο ± 0.55 (c=2.5, CHCl3).[α] D-11.1ο (c=0.18, CHCl3), Itokawa, H. et al. Chem. Pharm. Bull. 1985, 33, 1148.
$Konstantinos HatzellisGeorgia PagonaApostolos SpyrosManolis RoussakisMinistry <strong>of</strong> Education, GreeceRegion <strong>of</strong> CreteUniversity <strong>of</strong> CreteKostas DemetzosKostas Economakis