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Chapter VI: General Conclusion
In conclusion, we have demonstrated that new functionalized cationic [4]helicene dyes can be easily elaborated in a few steps from tris(2,6-dimethoxyphenyl) carbenium salt 6 in excellent purity and yields (up to 87%). These molecules were formed to study their biological properties by photophysical means. Along the way, novel surprising observations were made that showed that the side chains may have strong influences on processes that were deemed robust and fully trustworthy before!
First, the synthesis of water-soluble dyes was the focus of Chapter II. A variety of side chains were attached to the helical DMQA scaffold and afforded quite a few novel functionalized symmetrical and non-symmetrical derivatives. For instance, the introduction of short propyl (1a) and methyl (1b) side chains as well as polar OH (1c) and NH2 (1d) groups was performed in order to test their biological properties. This foreseen application required their resolution using the well-established protocol in the group, involving at the end the Pummerer fragmentation pathway due to the high stability of DMQA 1 cations.1 However, due to the sensitivity of the generated adducts 10, an immediate quench of the reaction was necessary to obtain good yields (82 to 95%). To our surprise, the presence of the methyl side chain had a dramatic effect on the chromatographic behavior of its neutral derivatives 10b compared to the easy separation of the diastereoisomers from the propyl DMQA 10a. This prompted us to study the effect of the side chains by synthesizing the hybrid Me-nPr-DMQA 1n. The study showed the influence on one hand of the substituent carried by the sp2 hybridized nitrogen atom of the DMQA moiety, on the
1H-NMR distribution of chemical shifts. On the other hand, the substituent of the pyramidalized sp3 nitrogen seemed to control the elution order of the neutral derivatives. The recourse to HPLC separation allowed after fine tuning of the conditions, a successful separation of adducts in good yields (82-95%). A thorough investigation involving solid state analysis vs the conformation in solution, the 1H and 13C-NMR spectra analysis and theoretical calculations was used to try to explain this behavior of a methyl group. With adducts separated, the enantiopure cations were regenerated via Pummerer fragmentation in 74-85% yields.
1 Laleu, B.; Mobian, P.; Herse, C.; Laursen, B. W.; Hopfgartner, G.; Bernardinelli, G.; Lacour, J. Angew. Chem., Inter. Ed. Engl. 2005, 44, 1879-1883. Laleu, B.; Machado, M. S.; Lacour, J. Chem. Commun. 2006, 2786-2788.
With the methyl 1b derivatives now available in racemic and enantiopure form, along with the already-known propyl 1a, a study of their biological properties through photophysical means was carried out in collaboration with the group of Prof. Eric Vauthey from the department of Physical Chemistry of the University of Geneva. It was shown that a stereoselective DNA binding mode was possible for this family of compounds with the strongest influence registered for the M enantiomer (Chapter III). Rather subtle effects were discovered using these compounds in water solutions and the formation of H aggregates in particular; something that had not been observed before in organic solvents.
In chapter IV, it was further demonstrated that cationic [4]helicenes can be functionalized with tailored, conformationally labile or “rigid” side chains containing azide functional groups at their ends. One or two such motifs were introduced around the helical cores and reacted with one or two biotin tags containing terminal alkynes functional groups. For this, a copper(I)-catalyzed 1,3-dipolar cycloaddition reaction between the azide on the cationic moieties and propargylic ester 29 and amide 31 derivatives of biotin was made of use. A photophysical study was also carried out with the group of Prof. Vauthey aiming this time at understanding the mechanisms at the surface and in the binding pocket of a protein, namely avidin/streptavidin which present an extremely strong binding affinity towards biotin – the highest value known in nature. The preliminary experiments were performed on the racemic series of the cations containing one biotin tag. One example with two tags was also studied. It was shown that the compounds with one biotin unit were more responsive to environment changes whereas the doubly tagged derivatives remained essentially unchanged. At the moment, work is still in progress.
Finally, some other projects were developed with molecules containing DMQA or TATA cores.
On one hand, an umpolung of DMQA derivatives from carbocations to carbanions was established. Optimised conditions were found to generate the anionic derivatives and yields of reactions with various electrophiles were improved from 41% to 82-92%. On the other hand, derivatives of TATA were synthesized in good yields using diamines and aminoalcohols of different lengths as nucleophiles. In an aim to use these scaffolds as tripodal ligands, a collaboration with the group of Dr. Joseph Hamacek of the department of Analytical and Applied Chemistry of the University of Geneva was established. A modified TATA with three free chelating groups was synthesized and employed to form a stable Europium complex.
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GENERAL REMARKS
All reactions involving air sensitive compounds were carried out under dry N2 or argon by means of an inert gas/vacuum double manifold line and standard Schlenk techniques. n-BuLi was titrated using N-benzylbenzamide in THF at –40°C prior to use. Solvents were dried being passed through activated alumina columns under a dry nitrogen atmosphere1 or distilled prior to use: dimethylformamide was freshly distilled over calcium hydride or bought from across in extra dry form. CDCl3 (SDS) was filtered on basic alumina prior to use. Analytical thin-layer chromatography (TLC) was performed with Merck SIL G/UV254 plates or Fluka 0.25 mm basic alumina (pH = 9.9) plates. Visualization of the developed chromatogram was performed by UV/VIS detection. Flash column chromatography (silicagel 60, 40 μm or Fluka basic alumina type 5016A) was performed in air or under pressure. Unless otherwise noted, all chemicals obtained commercially were purified according to standard literature procedures.1
Nuclear Magnetic Resonance (NMR) spectra were recorded on Bruker AMX-400 (or 300 or 500) at RT. 19F-NMR chemical shifts are given in ppm relative to CFCl3 (δ = 0). 1H NMR chemical shifts are given in ppm relative to Me4Si with the solvent resonance used as the internal standard. 13C NMR chemical shifts were given in ppm relative to Me4Si, with the solvent resonance used as the internal standard. Unless otherwise noted, the spectra were recorded at RT (298 K). Assignments have been achieved using COSY, INVIET and/or NOESY experiments.
Data were reported as follows: chemical shift (δ) in ppm on the chemical shift scale, multiplicity (s = singlet, d = doublet, dd = doublet of doublet, td = triplet of doublet, t = triplet, q = quartet and m = multiplet), coupling constant J (Hz), and integration (br = broad signal). Unless otherwise noted, the coupling constants concern proton-proton coupling.
IR spectra were recorded with a Perkin-Elmer 1650 FT-IR spectrometer using a diamond ATR Golden Gate sampling (cm-1).
Melting points (m.p.) were measured in open capillary tubes on a Büchi B-540 melting point apparatus and were uncorrected.
1 R. H. Grubbs and coll. Organometallics 1996, 15, 1518-1520; Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals, 4th ed., Pergamon Press: Oxford, 1997.
Electrospray mass spectra (ES-MS) were obtained on a Finnigan SSQ 7000 spectrometer by the Department of Mass Spectroscopy of the University of Geneva.
UV spectra were recorded on a CARY-1E spectrometer in a 1.0 cm quartz cell; λmax are given in nm and molar absorption coefficient ε in cm-1·dm3·mol-1.
Circular dichroism spectra were recorded on a JASCO J-715 polarimeter in a 1.0 cm quartz cell;
λ are given in nm and molar circular dichroic absorptions (Δε in M-1.cm-1).
Optical rotations were measured on a Perkin-Elmer 241 or a JASCO P-1030 polarimeter in a thermostated (20 °C) 10.0 cm long microcell at 589 nm (Na) or 435 nm (Hg) and are reported as follows: [ ]α λ20(c (g/100 ml), solvent).
HPLC analyses were performed on an Agilent 1100 apparatus (binary pump, autosampler, column thermostat and diode array detector).
The X-ray diffraction structures were solved at the “Laboratoire de Cristallographie aux rayons X” by Dr. G. Bernardinelli.
COMPOUNDS PREPARED ACCORDING TO LITERATURE PROCEDURES
9 Tris(2,6-dimethoxyphenyl)carbenium tetrafluoroborate salt 6.2 9 (+)-(R)-methyl-p-tolylsulfoxide or (+)-(R)-9.3
9 (rac)-methyl-p-tolylsulfoxide 9.
9 4,8,12-tri-n-propyl-4,8,12-triazatriangulenium tetrafluoroborate salt or [TATA][BF4] 2a.4 9 2-Amino-tert-butyldimethylsilyloxyethane.5
9 Tert-butyl (2-aminoethyl)carbamate 12.6 9 1,5 azidoaminopentane 23a.7
2 Wada, M.; Watanabe, T.; Natsume, S.; Mishima, H.; Kirishima, K.; Erabi, T. Bull. Chem. Soc. Jpn. 1995, 68, 3233.
3 Solladié, G.; Hutt, J.; Girardin, A. Synthesis 1987, 173.
4 Laursen, B. W.; Krebs, F. C. Angew. Chem. Int. Ed. 2000, 39, 3432-3434; Laursen, B. W. Ph. D. Thesis, Univ.
Copenhagen 2001, RisØ-R-1275 (EN).
5 Palomo, C.; Aizpurua, J.M. et al. Org. Lett 2007, 9 (1), 101-104.
6 Kilburn, J.D. et al. Chem. Eur. J. 2002, 8 (6), 1300-1309.
7 Kim, K. et al. Tetrahedron Lett. 2001, 42, 2709-2711.
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Chapter II: Resolution of cationic [4]helicenes through enantiopure sulfoxide addition
General procedure A for the synthesis of racemic dimethoxyquinacridinium salts or [rac-R-DMQA (1a-1j)] [BF4]:
At RT, the amine (98.0 mmol) was added to a solution of tris(2,6-dimethoxyphenyl)carbenium tetrafluoroborate [6][BF4] (2.00 g, 3.9 mmol) in N-methyl-2-pyrrolidone (NMP) (25 mL). The reaction mixture was heated at 110 °C for 1.5 h and then allowed to cool to RT. NMP was distilled off to afford a gummy compound which was washed several times with Et2O and filtered over Büchner funnel.
The titled compounds were further purified by (i) dissolution of crude product in CH2Cl2 and (ii) selective precipitation by addition of Et2O affording the desired racemic dimethoxyquinacridinium tetrafluoroborate salt (19F NMR (376 MHz, CD3CN) δ –151.7 (20%);
–151.8 (80%)).
General Procedure B for the synthesis of racemic dimethoxyquinacridinium salts or [rac-R-DMQA][PF6]:
At 25 °C, the amine (25 equiv.) was added to a solution of tris(2,6-dimethoxyphenyl)carbenium tetrafluoroborate [6][BF4] in 20mL NMP. The reaction mixture is heated at 90 °C for 4 h then allowed to cool down to RT. Addition of 100 mL of an aqueous solution of KPF6 afforded a precipitate which was filtered over Büchner funnel and washed thoroughly with water, then Et2O. The dark green gummy compound was then collected and dissolved in a minimum of dichloromethane and an excess of Et2O/Pentane was added for further purification. This selective precipitation process was repeated several times until the supernatant was colorless, to afford the desired dimethoxyquinacridinium salts as dark green solids in high yields (60-90%).
General procedure C for the sulfoxide addition and chromatographic separation of the resulting diastereomers (compounds 10a-m):
To a solution of diisopropylamine (1.82 mL, 13.0 mmol) in THF (10 mL) at 0 °C was added n-BuLi in hexane (8.7 mL, c 1.50 M, 13.0 mmol). After stirring at 0 °C for 30 min, a solution of (+)-(R)-methyl-p-tolylsulfoxide 9 (1.69 g, 11.0 mmol) in THF (10 mL) was added via cannula.
The resulting solution was stirred at 0 °C for 30 min and added via cannula to a suspension of rac-dimethoxyquinacridinium tetrafluoroborate salts 1 (10.0 mmol) in THF (200 mL). The solution was then allowed to warm up slowly to RT and after 14 h the reaction was quenched with H2O and extracted with Et2O. The organic layer was dried (Na2SO4) and concentrated in vacuo. A mixture of two diastereomers in a 1:1 ratio was obtained as monitored by 1H NMR.
Purification by chromatography (SiO2, 30 x 6.5 cm) with a gradient of Et2O/ Pentane (from 1:1 to a 4:1 mixture) allowed the separation of the two diastereomers as white solids having a ΔRf
range between 0.14-0.3, generally in good yields.
General Procedure D for the addition of the (+)-(R)-methyl-p-tolylsulfoxide and chromatographic separation of the resulting diastereoisomers (compounds 10b, 10n, 10q-r, 10v-x):
To a solution of diisopropylamine (0.067 mL, 0.48 mmol, 1.5 equiv.) in THF (2 mL) at 0 °C was added dropwise n-BuLi in nhexane (0.32 mL, c 1.48 M, 0.48 mmol) to form a fresh solution of LDA. After stirring at 0 °C for 30 min, a solution of (+)-(R)-methyl-p-tolylsulfoxide (74 mg, 0.48 mmol) in THF (2 mL) via cannula. The resulting solution is stirred for 30 min at 0 °C then added via cannula to a suspension of rac-dimethoxyquinacridinium salts (0.32 mmol, 200 mg) in THF (8 mL).
Immediate decoloration of the medium is observed. After 5 min, the TLC (Et2O 100% or Et2O/EtOAc: 70/30) shows the full conversion of the reaction to the desired diastereoisomers.
The medium is immediately quenched with water and extracted with Et2O or EtOAc. The organic layers are dried (Na2SO4), filtered and concentrated in vacuo at RT.
In the case of the symmetrical derivatives, a mixture of two diastereoisomers in a 1:1 ratio is obtained as monitored by 1H-NMR and HPLC. Purification by chromatography (SiO2, EtOAc/Et2O: 30/70) allowed the separation of the two diastereomeric fractions.
130 | P a g e General procedure E for the Pummerer fragmentation or the carbenium ion regeneration (compounds [M or P-DMQA][CF3CO2]):
Trifluoroacetic anhydride (2.3 mL, 16.2 mmol, 50 eq.) was added at 25 °C, to a solution of the sulfoxide derivative (0.3 mmol) in dichloromethane (5 mL). The initially colorless solution immediately turned blue-green. After 20 min, concentration in vacuo followed by several washings with Et2O afforded the crude product which was further purified over basic alumina (CH2Cl2 / MeOH: 97/3) to give the desired enantiopure salts. (Rf ~ 0.2)
Procedure F for the Pummerer fragmentation or carbenium ion regeneration (compounds [M or P-DMQA][Cl-]-1b):
At 25 °C, to a colorless solution of the diastereomerically pure sulfoxide derivative in Et2O is added dropwise, an excess of a commercially available solution of 1 M HCl in Et2O (100 equiv.).
The reaction is stirred between 6 h and overnight and its progress is monitored by TLC and MS.
The precipitation of the cation is observed after almost 30 minutes as dark green solid which is then filtered off and washed thoroughly with ether to remove the sulfoxide residues. Purification of the titled compound on a lipophilic sephadex column (Sigma Aldrich, CAS 9041-37-6, 25-100μ, LH20) afforded a clean compound as the enantiopure chloride salt in 74% yield.
Rac-1,13-dimethoxy-5,9-dipropyl-5,9-dihydroquinolino[2,3,4-kl]acridin-13b-ylium
tetrafluoroborate or [rac-nPr-DMQA][BF4] 1a: was synthesized following the general procedure A using n-propylamine (8.5 mL) to give (1.66 g, 3.31 mmol, 85%):
1H-NMR (500 MHz, CD3CN) δ 8.16 (t, 3J = 10.0 Hz,
IR 2969, 2940, 1605, 1582, 1502, 1343, 1265, 1176, 1091, 1049, 768; UV/VIS (CH2Cl2, 1.10–5 M, λmax (log ε)) = 617 (4.40), 438 (4.00), 312 (4.89), 284 (4.60), 261 (4.61), 241 (4.57), 227 (4.61); m.p. 354 °C (decomposition); MS (ESI+, m/z) 413.5.
Rac-1,13-dimethoxy-5,9-dimethyl-5,9-dihydroquinolino[2,3,4-kl]acridin-13b-ylium
tetrafluoroborate salt or [rac-Me-DMQA][BF4] 1b was synthesized following the general procedure A using methylamine (2.5 mL) to give (1.04 g, 2.34 mmol, 80%):
1H-NMR (500 MHz, CD3CN) δ 8.14 (t, 3J = 8.5 Hz, 1H, H-CAr (7)), 7.89 (t, 3J = 8.2 Hz, 2H, H-CAr(3/11)), 7.49 (d, 3J = 8.5 Hz, 2H, H-C(6/8)), 7.45 (d, 3J = 8.5 Hz, 2H, H-C(4/10)), 6.92 (d, 3J = 8.2 Hz, 2H, H-C(2/12)), 4.08 (s, 6H, 2x CH3 N), 3.73 (s, 6H, 2x CH3 O). 13C-NMR (125 MHz, CD3CN) δ 160.2 (C), 143.8 (C), 143.1 (C), 140.4 (C), 137.9 (CH(3/11)), 137.2 (CH(7)), 114.1 (C), 108.7 (CH(4/10)), 106.0 (CH(6/8)), 104.2 (CH(2/12)), 56.5 (C(1/13)-OCH3), 38.3 (N(5/9)-CH3); IR 2969, 2940, 1605, 1582, 1502, 1343, 1265, 1176, 1091, 1049, 768;
UV/VIS (CH2Cl2, 9.9 x 10–6 M, λmax (log ε)) = 615 (4.09), 436 (4.74), 311 (4.60), 282 (4.35),
132 | P a g e Rac-1,13-dimethoxy-5-methyl-9-propyl-5,9-dihydroquinolino[2,3,4-kl]acridin-13b-ylium
hexafluorophosphate(V) or [rac-Me-nPr-DMQA][PF6] 1n was synthesised following procedure B from methyl acridinium 3n in 70% yield.
1H-NMR (400 MHz, CDCl3) δ 8.19 (t, 3J = 10.0 Hz, H-C(7), 1H), 7.95-7.85 (m, H-C(3/11), 2H), 7.52-7.32 (m, H-C(4/10), 4H), 6.90-6.82 (m, H-C(2/12), 2H), 4.70-4.58 (m, F-NMR –72.17/–73.67 IR 2937, 1605, 1582, 1522, 1502, 1468, 1345, 1253, 1175, 1092, 834, 761;
UV/VIS (CH2Cl2, 1.10–5 M, λmax (log ε)) = 616 (4.22), 438 (3.85), 311 (4.71), 283 (4.44), 261 (4.48), 227 (4.52). MS (ESI+, m/z) 385.5.
Rac-5,9-bis-(2-hydroxyethyl)-1,13-dimethoxy-5,9-dihydroquinolino[2,3,4-kl]acridin-13b-ylium tetrafluoroborate or [rac-HO(CH2)2-DMQA][BF4] 1c:
At RT, ethanolamine (5.98 g, 98.0 mmol) was added to a solution of tris(2,6-dimethoxyphenyl)carbenium tetrafluoroborate [6][BF4] (2.00 g, 3.9 mmol) in NMP (25 mL). The reaction mixture was heated at 110 °C for 1 h and then NMP and the non-reacted ethanolamine were distilled off under reduced pressure (110°C, 15 mmHg). The residual green oil was washed with Et2O (~25 mL) to afford a precipitate which was filtered over Büchner funnel and collected. The titled compound was further purified by (i) dissolution of the crude product in CH2Cl2 and (ii)
O
selective precipitation by addition of Et2O affording the titled compound 1c (1.68 g, 3.33 mmol, 85%).
1H NMR (CD3CN, 400 MHz) δ 8.08 (t, 3J = 8.6 Hz, 1H), 7.86 (t, 3J = 8.3 Hz, 2H), 7.66 (d, 3J = 8.6 Hz, 2H), 7.53 (d, 3J = 8.8 Hz, 2H), 6.89 (d, 3J = 8.1 Hz, 2H), 4.84-4.77 (m, 2H), 4.67-4.59 (m, 2H), 4.13 (m, 4H), 3.71 (s, 6H), 3.31 (s, br, 2H); 13C NMR (CD3CN, 100 MHz) δ 160.5 (C), 143.9 (C), 143.7 (C), 140.3 (C), 137.8 (CH), 137.0 (CH), 120.3 (C), 113.9 (C), 109.0 (CH), 106.7 (CH), 103.9 (CH), 59.3 (CH2), 56.5 (CH3), 52.4 (CH2); m.p. 280 °C; IR 3530, 2947, 1605, 1580, 1500, 1470, 1344, 1254, 1150, 1045, 765; UV/VIS (CH2Cl2, 9.91 x 10–6 M, λmax (log ε)) = 617 (4.26), 442 (3.92), 312 (4.77), 284 (4.48), 262 (4.51), 242 (4.46), 227 (4.57); MS (ESI+, m/z) 417.4.
Rac-5,9-bis-(2-aminoethyl)-1,13-dimethoxy-5,9-dihydroquinolino[2,3,4-kl]acridin-13b-yliumtetrafluoroborate or [rac-NH2(CH2)2-DMQA][BF4] 1d: was synthesized following the general procedure A using ethylenediamine (2 mL) to give (384 mg, 0.76 mmol, 65%):
1H NMR (500 MHz, CD3CN) δ 8.15 (t, 3J = 10 Hz, 1H), 7.88 (t, 3J = 10 Hz, 2H), 7.64 (d, 3J = 10 Hz, 2H), 7.55 (d, 3J
= 5 Hz, 2H), 6.90 (d, 3J = 5 Hz, 2H), 4.71-4.65 (m, 2H), 4.50-4.44 (m, 2H), 3.70 (s, 6H), 3.42-3.12 (m, 4H), 2.32-2.17 (br s, 2H); 13C NMR (CD3CN, 125 MHz) δ 160.5 (C), 143.6 (C), 143.4 (C), 140.1 (C), 137.8 (CH), 137.2 (CH), 113.9 (C), 108.7 (CH), 106.3 (CH), 103.9 (CH), 56.5 (CH3), 53.3 (CH2), 39.3 (CH2); m.p. 145 °C; IR 3350, 2980, 1606, 1583, 1502, 1346, 1251, 1174, 765; UV/VIS (CH2Cl2, 1.10–5 M, λmax (log ε)) = 619 (4.58), 578 (4.44), 438 (4.22), 312 (5.06); MS (ESI+, m/z) 415.5.
BF4 O
N N
O
NH2 H2N
Chemical Formula: C25H27BF4N4O2 Molecular Weight: 502.31
134 | P a g e
Rac-5,9-bis(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,13-dimethoxy-5,9-dihydroquinolino[2,3,4-kl]acridin-13b-ylium tetrafluoroborate or [rac-TBSO(CH2)2-DMQA][BF4] 1e: was synthesized from the diol 1c. Under argon, 1c (2g, 3.96 mmol, 1 equiv.) was dissolved in 15 mL of dry DMF, in the presence of imidazole (3.24g, 47.6 mmol, 12 equiv.). To this solution, tert-butylchlorodimethylsilane (TBSCl) was added (3.59g, 6 equiv.) and the medium was stirred for 24 h at RT. The crude mixture was then quenched with water and extracted 3 times with CH2Cl2. The aqueous layers were washed with brine, dried with Na2SO4, filtered and concentrated in vacuo. The blue-green gummy compound collected was then purified by chromatography over silica gel (20 x 0.5 cm, CH2Cl2/MeOH 95:5) to afford the titled compound (1.89 g, 65% yield). 227.9-228.5 °C; IR 3530, 2947, 2896, 2850, 1605, 1580, 1557, 1500, 1470, 1344, 1254, 1150, 1045, 813, 765; UV/VIS (CH2Cl2, 9.55 x 10-6 M, λmax (log ε)) = 618 (4.10), 445 (3.78), 312 (4.60), 284 (4.33); MS (ESI+, m/z) 646.0.
Rac-5,9-bis(2-((tert-butoxycarbonyl)amino)ethyl)-1,13-dimethoxy-5,9-dihydroquinolino[2,3,4-kl]acridin-13b-ylium tetrafluoroborate or [rac-NHBoc(CH2)2 -DMQA][BF4] 1f: was synthesized following the general procedure A using tert-butyl (2-aminoethyl)carbamate 12 (4.49 g, 28.0 mmol, 25 equiv.) to give (592 mg, 0.9 mmol, 75%):
from 1c with the following procedure :
At RT, to a solution of [HO(CH2)2-DMQA][BF4] 1c (1.0 g, 2.0 mmol) in dichloromethane (20 mL) was added Et3N (1.2 mL, 8.8 mmol) followed by methanesulfonyle chloride CH3SO2Cl (0.7 mL, 8.8 mmol). The medium is heated to reflux (40°C) for 3-4 h and the reaction evolution is followed by TLC (CH2Cl2/ MeOH: 95/5, Rf = 0.37) and MS. The reaction is cooled down to RT, then water is added to neutralize excess of mesyle chloride; after a washing with 30 mL of a 0.1M solution of citric acid and 20 mL of water, the medium was extracted in dichloromethane and dried with sodium sulfate. Evaporation of the solvent yielded the product (964 mg, 1.5 mmol, 73%) as a green solid: (decomposition); IR 2943, 1727, 1604, 1581, 1502, 1342, 1265, 1171, 1050, 763; UV/VIS (CH2Cl2, 1.10–5 M, λmax (log ε)) = 612 (4.78), 573 (4.60), 442 (4.47), 310 (5.0); MS (ESI+, m/z)
136 | P a g e Rac-5,9-bis(2-azidoethyl)-1,13-dimethoxy-5,9-dihydroquinolino[2,3,4-kl]acridin-13b-ylium tetrafluoroborate or [rac-N3(CH2)2-DMQA][BF4] 1m: was synthesized by a nucleophilic substitution of 1l with NaN3. At RT, compound 1l (2.6 g, 4.0 mmol) was dissolved in 20 mL of freshly distilled DMF. Sodium azide (2.6 g, 40.0 mmol) is then added and the mixture was stirred for 3 days.
After checking reaction completion by TLC (Rf = 0.7 in CH2Cl2/MeOH: 95/5) and MS, water was added (40 mL) and the medium was extracted (3 x) with dichloromethane (150 mL). The organic layers were washed with 20mL of brine then dried with sodium sulfate. Solvent removal under vacuo provided the crude that was further purified by 3-4 recrystallisations in CH3CN/ Et2O and a preparative TLC (eluent: CH2Cl2/ MeOH: 95/5, Rf = 0.7) to yield (1.2 g, 2.2 mmol, 55%) as a green solid. Note that on a smaller scale, a yield of 94% was obtained relative to 200 mg of product:
1H NMR (300 MHz, (CD3)2CO) δ 8.40 (t, 3J = 8.7 Hz, 1H), 8.08 (d, 3J = 8.1 Hz, 2H), 8.01 (d, 3J Rac-5,9-bis(3-aminopropyl)-1,13-dimethoxy-5,9-dihydroquinolino[2,3,4-kl]acridin-13b-ylium tetrafluoroborate or [rac-NH2(CH2)3 -DMQA][BF4] 1h: was synthesized following the general procedure A, using 1,3-diaminopropane (0.5 mL, 5.0 mmol) to give (77 mg, 0.14 mmol, 72%).
105.9 (CH), 103.9 (CH), 56.4 (CH3), 48.9 (CH2), 39.8 (CH2), 29.8 (CH2); m.p. 210 °C; IR 3010, 2350, 1606, 1583, 1501, 1345, 1252, 1173, 1060, 764; MS (ESI+, m/z) 443.6.
Rac-5,9-bis(4-aminobutyl)-1,13-dimethoxy-5,9-dihydroquinolino[2,3,4-kl]acridin-13b-ylium tetrafluoroborate or [rac-NH2(CH2)4 -DMQA][BF4] 1i: was synthesized following the general procedure A using putrescine or 1,4-diaminobutane (1.25 mL, 12.5 mmol) to give (100 mg, 0.2 mmol, 36 %).
138 | P a g e (CH3), 50.8 (CH2), 41.8 (CH2), 31.3 (CH2), 27.0 (CH2), 26.9 (CH2), 26.8 (CH2); m.p. 191 °C; IR 2940, 1606, 1583, 1501, 1345, 1265, 1173, 763; MS (ESI+, m/z) 527.4.
Tert-butyl 2-(1,3-dioxoisoindolin-2-yl)ethylcarbamate 14:
Phtalic anhydride (2 g, 12.5 mmol, 1 eq) and tert-butyl (2-aminoethyl) carbamate 12 (1.7 g, 11.3 mmol, 1.1 eq) were heated together in the absence of solvent to 130 °C, with a distillation head to remove the water formed from the reaction. The mixture turns from white to an oily yellow. After 1 h, the medium is cooled down to RT, and methanol is added to precipitate the product as a white solid that is soluble in hot DMSO. (60%, 2 g) 2-(1,3-dioxoisoindolin-2-yl)ethylcarbamate 14 (200 mg, 0.7 mmol) in 3.3 mL of EtOH under vigorous stirring, is added dropwise 2.5 mL of commercial HCl.Et2O until solubilisation. After a few minutes, a precipitate is formed and the desired product is recovered by filtration as a hydrochloric salt in quantitative yield.
2-(2-aminoethyl)isoindoline-1,3-dione trifluoroacetate 15:
To a solution of tert-butyl 2-(1,3-dioxoisoindolin-2-yl)ethylcarbamate (200 mg, 0.7 mmol) in CH2Cl2 is added an excess of trifluoroacetic acid. The solution is left stirring overnight at RT. The reaction progress is followed by TLC (Et2O) Rf = 0.1 and MS (191+). The medium was concentrated to afford a white solid and the crude was washed with a small volume of a 0.1 M solution of sodium carbonate; the product is obtained as a trifluoroacetate (104 mg, 100%).
1H NMR ((CD3)2SO, 300 MHz) δ 7.92-7.82 (m, 4H), 3.84 (t, 3J = 5.7 Hz, 2H), 3.10-3.06 (m, 2H); 19F NMR ((CD3)2SO, 376 MHz) δ -75.0; MS (ESI+, m/z) 191.
(–)-(R,M)-1,13-dimethoxy-5,9-dipropyl-13b-((p-tolylsulfinyl)methyl)-9,13b-dihydro-5H-quinolino[2,3,4-kl]acridine or (–)-(R,M)-10a:
Most eluted fraction (SiO2, Et2O, Rf (Et2O) = 0.63) using the general procedure C, 45% yield (m = 22 mg);
1H-NMR (500 MHz, CDCl3) δ 7.17 (t, 3J = 10.0 Hz, 1H, H-C(7/11)), 7.17 (t, 3J = 10.0 Hz, 1H, H-C(7/11)), 7.07 (t, 3J = 10.0 Hz, 1H, H-C(3)), 7.03 (d, 3J = 10.0Hz, 2H, pTol(m)), 6.97 (d, 3J = 10.0 Hz, 2H, pTol(o)), 6.78 (d, 3J = 10.0 Hz, 1H, H-C(4)), 6.68 (d, 3J = 10.0 Hz, 1H, H-C(6)), 6.55 (d, 3J = 10.0 Hz, 1H, H-C(8)), 6.54 (d, 3J = 10.0 Hz, 1H, H-C(10)), 6.45 (d, 3J = 10.0 Hz, 1H, H-C(2)), 6.24 (d, 3J = 10.0 Hz, 1H, H-C(12)), 4.14 (d, J = 15.0 Hz, 1H, CH2SO), 4.06-3.90 (m, 2H, NCH2CH2CH3), 3.85-3.65 (m, 2H, NCH2CH2CH3), 3.69 (d, J = 15.0 Hz, 1H, CH2SO), 3.49 (s, 3H, OMe), 3.28 (s, 3H, OMe), 2.29 (s, 3H, Me pTol), 2.08-1.95 (m, 2H, NCH2CH2CH3), 1.92-1.75 (m, 2H, NCH2CH2CH3), 1.08 (t,
3J = 5.0 Hz, 3H, NCH2CH2CH3), 1.07 (t, 3J = 5.0 Hz, 3H, NCH2CH2CH3); 13C-NMR (125 MHz, CDCl3) δ 160.5 (C), 157.6 (C), 143.8 (C), 143.6 (C), 142.7 (C), 140.6 (C), 140.1 (C), 138.7 (C), 129.2 (CH, pTol), 128.6 (CH), 127.5 (CH), 126.1 (CH), 124.5 (CH, pTol), 116.7 (C), 111.2 (C), 110.8 (CH), 107.6 (CH), 106.2 (CH), 105.8 (CH), 105.7 (CH), 105.2 (CH), 101.3 (CH), 67.7 (CH2, CH2SO), 56.2 (CH3), 54.5 (CH3), 48.9 (CH2, NCH2CH2CH3), 48.4 (CH2, NCH2CH2CH3), 39.3 (C), 30.4 (C), 21.4 (CH3 pTol), 20.5 (CH2, NCH2CH2CH3), 20.1 (CH2, NCH2CH2CH3), 12.1
140 | P a g e (CH3, NCH2CH2CH3), 11.2 (CH3, NCH2CH2CH3); m.p. 86 °C; IR 2960, 2872, 1610, 1585, 1474, 1380, 1129, 1031, 781, 731 cm-1; UV/VIS (CH2Cl2, 1.10-5 M, λmax (log ε)) = 330 (4.25), 289 (4.24); CD (CH2Cl2, 1.10-5 M, 20 °C) λ (Δε) 331 (–53.2), 279 (–19.2), 246 (–34.1); [α]20D = – 710 (c = 0.056, CH2Cl2).
(+)-(R,P)-1,13-dimethoxy-5,9-dipropyl-13b-((p-tolylsulfinyl)methyl)-9,13b-dihydro-5H-quinolino[2,3,4-kl]acridine or (+)-(R,P)-10a:
Least eluted fraction (SiO2, Et2O, Rf (Et2O) = 0.27) using the general procedure C, 45% yield (22 mg).
1H-NMR (500 MHz, CDCl3) δ 7.28 (t, 3J = 10.0 Hz, 1H, H-C(11)), 7.07 (t, 3J = 10.0 Hz, 1H, H-C(3)), 7.02 (t, 3J = 10.0 Hz, 1H, H-C(7)), 7.00 (d, 3J = 10.0Hz, 2H, pTol(m)), 6.83 (d, 3J = 10.0 Hz, 2H, pTol(o)), 6.70 (d, 3J = 10.0 Hz, 1H, H-C(4)), 6.56 (d, 3J = 10.0 Hz, 1H, H-C(10)), 6.55 (d, 3J = 10.0 Hz, 1H, H-C(12)), 6.49 (d, 3J = 10.0 Hz, 1H, H-C(2)), 6.45 (d, 3J = 10.0 Hz, 1H, H-C(6)), 6.32 (d, 3J = 10.0 Hz, 1H, H-C(8)), 4.02 (d, J = 15.0 Hz, 1H, CH2SO), 3.98 (d, J = 15.0 Hz, 1H, CH2SO), 3.84 (s, 3H, OMe), 3.82-3.55 (m, 4H, NCH2CH2CH3), 3.34 (s, 3H, OMe), 2.32 (s, 3H, Me pTol), 1.85-1.68 (m, 3H, NCH2CH2CH3), 1.67-1.55 (m, 1H, NCH2CH2CH3), 1.04 (t, 3J = 10.0 Hz, 3H, NCH2CH2CH3), 0.94 (t, 10.0 Hz, 3H, NCH2CH2CH3). 13C-NMR (125 MHz, CDCl3) δ 161.5 (C), 157.5 (C), 143.5 (C), 142.9 (C), 142.5 (C), 140.4 (C), 140.2 (C), 138.7 (C), 130.1 (CH), 129.2 (CH, pTol), 129.0 (CH), 126.8 (CH), 126.2 (CH), 124.6 (CH, pTol), 117.2 (C), 111.5 (C), 110.8 (CH), 107.5 (CH), 106.5 (CH), 105.6 (CH), 105.1 (CH), 104.8 (CH), 102.2 (CH), 67.8 (CH2, CH2SO), 56.2 (CH3), 55.3 (CH3), 49.0 (CH2, NCH2CH2CH3), 48.1 (CH2, NCH2CH2CH3), 38.9 (C), 30.4 (C), 21.4 (CH3 pTol), 20.4 (CH2, NCH2CH2CH3), 20.0 (CH2, NCH2CH2CH3), 11.9 (CH3, NCH2CH2CH3), 11.1 (CH3, NCH2CH2CH3); m.p. 78 °C; UV/VIS (CH2Cl2, 1.10-5 M, λmax
(log ε)) = 330 (4.25), 289 (4.24); CD (CH2Cl2, 1.10-5 M, 20 °C) λ (Δε) 331 (52.8), 280 (45.3), 250 (46.3), 230 (–64.9); [α]20D = + 820 (c = 0.056, CH2Cl2).
(–)-(R,M)-13b-Methanesulfinyl-p-tolyl-1,13-dimethoxy-5,9-bis-[2-azido-ethyl]-9,13b-dihydro-5H-5,9-diaza-naphtho-[3,2,1-de] anthracene or (–
)-(R,M)-10m:
Most eluted fraction Preparative TLC (SiO2, Et2O/Pentane (90:10), Rf = 0.33) using the general procedure C starting from 0.2 mmol (100 mg) of the dimethoxyquinacridinium tetrafluoroborate salt, 13 % yield (7 mg):
1H NMR (300 MHz, CD2Cl2) δ 7.32 (t, 3J = 8.2 Hz, 1H), 7.22 (t, 3J = 8.2 Hz, 1H), 7.12-7.06 (m, 3H), 6.99 (d, 3J = 8.2 Hz, 2H), 6.72 (d, 3J = 8.5 Hz, 2H), 6.66 (d, 3J = 8.2 Hz, 2H), 6.52-6.47 (m, 2H), 4.21-4.00 (m, 4H), 3.88-3.80 (m, 4H), 3.75-3.66 (m, 2H), 3.61 (s, 3H), 3.33 (s, 3H), 2.30 (s, 3H); IR 2095 (N3).
(+)-(R,P)-13b-Methanesulfinyl-p-tolyl-1,13-dimethoxy-5,9-bis-[2-azido-ethyl]-9,13b-dihydro-5H-5,9-diaza-naphtho-[3,2,1-de] anthracene or (+)-(R,P)-10m:
Least eluted fraction Preparative TLC (SiO2, Et2O/Pentane (90:10), Rf = 0.19) using the general procedure C starting from 0.2 mmol (100 mg) of the dimethoxyquinacridinium tetrafluoroborate salt, 10 % yield (5 mg):
1H NMR (CDCl3, 400 MHz) δ 7.35 (t, 3J = 8.4 Hz, 1H), 7.18-7.06 (m, 4H), 6.78 (d, 3J = 8.1 Hz, 2H), 6.69-6.62 (m, 3H), 6.58-6.52 (m, 3H), 4.05-3.97 (m, 4H), 3.82 (s, 3H), 3.68 (t, 3J = 7.4 Hz, 2H), 3.42-3.37 (m, 4H), 3.36 (s, 3H), 2.33 (s, 3H); IR 2098 (N3).
O O
p-Tol S
O
N N
N3 N3
(R)
starting from 0.2 mmol of the dimethoxyquinacridinium tetrafluoroborate salt, 45% yield (410 mg).
1H NMR (CDCl3, 400 MHz) δ 7.19 (dd, 3J = 7.8 Hz, 3J = 7.6 Hz, 2H), 7.09-7.02 (m, 3H), 6.96 procedure C starting from 0.2 mmol of the dimethoxyquinacridinium tetrafluoroborate salt, 49%
(–)-(R,M)-1,13-dimethoxy-5,9-dimethyl-13b-((p-tolylsulfinyl)methyl)-9,13b-dihydro-5H-quinolino[2,3,4-kl]acridine or (–)-(R,M)-10b: was synthesized following the general procedure D using 0.45 mmol (0.2 g) of rac-[DMQA][BF4] 1b. Most eluted fraction (regular achiral nucleosil column (Macherey Nagel, SP 250/10 Nucleosil 50-7) with nhexane/iPrOH 90:10 as eluent (flow 3 mL/min, 23 °C, P = 39 bars, 200 μL per injection) 41% yield.
1H-NMR (500 MHz, CDCl3) δ 7.20 (t, 3J = 10.0 Hz, 1H, H-C(7/11)), 7.19 (t, 3J = 10.0 Hz, 1H,
144 | P a g e 105.6 (CH), 104.9 (CH), 101.5 (CH), 67.6 (CH2), 56.0 (CH3), 54.5 (CH3), 39.4 (C), 34.1 (CH3), 21.2 (CH3); IR 2955, 2833, 1587, 1480, 1436, 1373, 1342, 1249, 1171, 1137, 1088, 1056, 782, 735; UV/VIS (CH2Cl2, 0.92 x 10–5 M, λmax (log ε)) = 328 (4.42), 312 (4.44), 249 (4.80); CD (CH2Cl2, 0.92 x 10–5 M, 20 °C) λ (Δε) 327 (–110.6), 293 (+18.4), 274 (–51.5), 261 (–23.6), 244 (–91.5); [α]58920= – 842 (c = 0.0092, CH2Cl2).
(+)-(R,P)-1,13-dimethoxy-5,9-dimethyl-13b-((p-tolylsulfinyl)methyl)-9,13b-dihydro-5H-quinolino[2,3,4-kl]acridine or (+)-(R,P)-10b: was synthesized following the general procedure D using 0.45 mmol (0.2 g) of rac-[DMQA][BF4] 1b. Least eluted fraction (regular achiral nucleosil column (Macherey Nagel, SP 250/10 Nucleosil 50-7) with
nhexane/iPrOH 90:10 as eluent (flow 3 mL/min, 23 °C, P = 39 bars, 200 μL per injection) 41% yield.
1H-NMR (500 MHz, CDCl3) δ 7.30 (t, 3J = 10.0 Hz, 1H, H-C(3/11)), 7.10 (t, 3J = 10.0 Hz, 1H, H-C(3/11)), 7.00 (t, 3J = 10.0 Hz, 1H, H-C(7)), 6.97 (d, 3J = 10.0Hz, 2H, pTol(m)), 6.82 (d, 3J = 10.0 Hz, 2H, pTol(o)), 6.68 (d, 3J = 10.0 Hz, 1H, H-C(4)), 6.58 (d, 3J = 10.0 Hz, 1H, H-C(10)), 6.56 (d, 3J = 10.0 Hz, 1H, H-C(12)), 6.52 (d, 3J = 10.0 Hz, 1H, H-C(2)), 6.41 (d, 3J = 10.0 Hz, 1H, H-C(6)), 6.24 (d, 3J = 10.0 Hz, 1H, H-C(8)), 4.06 (d, J = 15.0 Hz, 1H, CH2SO), 3.90 (d, J = 15.0 Hz, 1H, CH2SO), 3.86 (s, 3H, OMe), 3.38 (s, 3H, NMe), 3.38 (s, 3H, OMe), 3.21 (s, 3H, NMe), 2.32 (3H, s, Me pTol); 13C-NMR (125 MHz, CDCl3) δ 161.4 (C), 157.1 (C), 144.4 (C), 142.8 (C), 141.7 (C), 140.9 (C), 140.4 (C), 138.9 (C), 129.0 (CH, pTol), 128.9 (CH), 126.7 (CH), 126.4 (CH), 124.9 (CH, pTol), 116.7 (C), 111.1 (C), 110.8 (C), 106.5 (CH), 106.4 (CH), 105.7 (CH), 105.0 (CH), 104.1 (CH), 102.1 (CH), 67.4 (CH2, CH2SO), 56.0 (CH3, OMe), 55.2 (CH3, OMe), 38.8 (C), 34.1 (CH3, NMe), 34.0 (CH3, NMe), 21.3 (CH3 pTol). IR 2955, 2833, 1587, 1480, 1436, 1373, 1342, 1249, 1171, 1137, 1088, 1056, 782, 735; UV/VIS (CH2Cl2, 1.10–5 M, λmax (log ε)) = 328 (4.43), 312 (4.46), 249 (4.82); CD (CH2Cl2, 1.10–5 M, 20 °C) λ (Δε) 328 (+96.4), 300 (+1.09), 278 (+95.8), 261 (+45.2), 248 (+92.0); [α]20589= +457 (c = 0.0116, CH2Cl2).
(–)-(RS ,M,S)-1,13-dimethoxy-5-methyl-9-propyl-13b-(((R)-p-tolylsulfinyl)methyl)-9,13b-dihydro-5H-quinolino[2,3,4-kl]acridine or (–)-(R, M1)-10n was synthesized according to general procedure D using 0.19 mmol (0.1 g) of rac-[DMQA][BF4] 1n. Most eluted fraction of M helicity (SiO2, with Et2O/pentane 80:20 as eluent, Rf = ,M,R)-1,13-dimethoxy-5-methyl-9-propyl-13b-(((R)-p-tolylsulfinyl)methyl)-9,13b-dihydro-5H-quinolino[2,3,4-kl]acridine or (–)-(R, M2)-10n was synthesized according to general procedure D using 0.19 mmol (0.1 g) of rac-[DMQA][BF4] 1n. Least eluted fraction of M helicity. First eluted fraction using MTBE/EtOH 95/5 analytical IB (Daicel) 23 °C, 6 μL injection, to afford 18 mg (18 % yield).
146 | P a g e
1H-NMR (500 MHz, CDCl3) δ 7.19 (t, 3J = 10.0 Hz, 1H, H-C(7)), 7.18 (t, 3J = 10.0 Hz, 1H, H-C(11)), 7.09 (t, 3J = 10.0 Hz, 1H, H-C(3)), 7.03 (d, 3J = 10.0Hz, 2H, pTol(m)), 6.95 (d, 3J = 10.0 Hz, 2H, pTol(o)), 6.73 (d, 3J = 10.0 Hz, 1H, H-C(4)), 6.62 (d, 3J = 10.0 Hz, 1H, H-C(6)), 6.57 (d,
3J = 10.0 Hz, 1H, H-C(8)), 6.56 (d, 3J = 10.0 Hz, 1H, H-C(10)), 6.48 (d, 3J = 10.0 Hz, 1H, H-C(2)), 6.25 (d, 3J = 10.0 Hz, 1H, H-C(12)), 4.19 (d, J = 15.0 Hz, 1H, CH2SO), 3.85-3.66 (2H, m, NCH2CH2CH3), 3.65 (d, J = 15.0 Hz, 1H, CH2SO), 3.54 (s, 3H, NMe), 3.49 (s, 3H, OMe), 3.29 (s, 3H, OMe), 2.29 (s, 3H, Me pTol), 1.92-1.75 (m, 2H, NCH2CH2CH3), 1.06 (t, 3J = 10.0 Hz, 3H, NCH2CH2CH3); 13C-NMR (125 MHz, CDCl3) δ 160.4 (C), 157.4 (C), 144.6 (C), 143.3 (C), 140.6 (C), 140.0 (C), 138.4 (C), 129.0 (CH, pTol), 128.6 (CH), 127.6 (CH), 126.3 (CH), 124.4 (CH, pTol), 116.1 (C), 111.1 (C), 110.1 (C), 106.6 (CH), 106.4 (CH), 105.7 (CH), 105.3 (CH), 104.9 (CH), 101.2 (CH), 67.6 (CH2, CH2SO), 56.1 (CH3), 54.4 (CH3), 48.7 (CH2, NCH2CH2CH3), 39.3 (C), 34.2 (CH3), 21.3 (CH3 pTol), 19.9 (CH2, NCH2CH2CH3), 11.0 (CH3, NCH2CH2CH3); IR 2958, 2873, 1613, 1586, 1475, 1436, 1384, 1343, 1234, 1178, 1126, 1087, 1055, 952, 810, 780, 733; UV/VIS (CH2Cl2, 2.8 x 10–5 M, λmax (log ε)) = 328 (3.94), 281 (3.95), 248 (4.27); CD (CH2Cl2, 2.8 x 10–5 M, 20 °C) λ (Δε) 329 (–35.5), 292 (+3.3), 275 (–14.8), 261 (–5.8), 243 (–27.2); [α]20589= – 432 (c = 0.0298, CH2Cl2).
(+)-(RS ,P,S)-1,13-dimethoxy-5-methyl-9-propyl-13b-(((R)-p-tolylsulfinyl)methyl)-9,13b-dihydro-5H-quinolino[2,3,4-kl]acridine or (+)-(R, P3)-10n was synthesized according to general procedure D using 0.19 mmol (0.1 g) of rac-[DMQA][BF4] 1n. Most eluted fraction of P helicity. Second eluted fraction using MTBE/EtOH 95/5 analytical IB (Daicel) 23 °C, 6 μL injection to afford 19 mg of P3 in 19 % yield.
1H-NMR (500 MHz, CDCl3) δ 7.29 (t, 3J = 10.0 Hz, 1H, H-C(11)), 7.07 (t, 3J = 10.0 Hz, 1H, H-C(3)), 6.99 (t, 3J = 10.0 Hz, 1H, H-C(7)), 6.97 (d, 3J = 10.0Hz, 2H, pTol(m)), 6.80 (d, 3J = 10.0 Hz, 2H, pTol(o)), 6.71 (d, 3J = 10.0 Hz, 1H, H-C(4)), 6.59 (d, 3J = 10.0 Hz, 1H, H-C(10)), 6.56 (d, 3J = 10.0 Hz, 1H, H-C(12)), 6.49 (d, 3J = 10.0 Hz, 1H, H-C(2)), 6.46 (d, 3J = 10.0 Hz, 1H, H-C(6)), 6.25 (d, 3J = 10.0 Hz, 1H, H-C(8)), 4.02 (d, J = 15.0 Hz, 1H, CH2SO), 3.91 (d, J = 15.0 Hz, 1H, CH2SO), 3.85 (s, 3H, OMe), 3.82-3.73 (m, 2H,
NCH2CH2CH3), 3.36 (s, 3H, OMe), 3.24 (s, 3H, NMe), 2.31 (s, 3H, Me pTol), 1.82-1.60 (m, 2H, NCH2CH2CH3), 0.95 (t, 3J = 10.0 Hz, 3H, NCH2CH2CH3); 13C-NMR (125 MHz, CDCl3) δ 161.3 (C), 157.3 (C), 143.4 (C), 142.2 (C), 142.0 (C), 141.0 (C), 140.3 (C), 139.1 (C), 128.9 (CH), 128.9 (CH, pTol), 126.5 (CH), 126.1 (CH), 124.7 (CH, pTol), 117.1 (C), 111.5 (C), 110.9 (C), 107.4 (CH), 106.1 (CH), 105.7 (CH), 105.0 (CH), 104.9 (CH), 102.2 (CH), 67.6 (CH2, CH2SO), 56.0 (CH3), 55.2 (CH3), 48.1 (CH2, NCH2CH2CH3), 38.8 (C), 34.2 (CH3), 21.3 (CH3
pTol), 20.3 (CH2, NCH2CH2CH3), 11.8 (CH3, NCH2CH2CH3); IR 2960, 2932, 2829, 1585, 1475, 1435, 1371, 1242, 1168, 1140, 1093, 1058, 1033, 810, 781,734; UV/VIS (CH2Cl2, 2.5 x 10–5 M, λmax (log ε)) = 330 (4.06), 285 (4.11), 249 (4.41); CD (CH2Cl2, 2.5 x 10–5 M, 20 °C) λ (Δε) 329 (+41.4), 300 (+6.8), 277 (+34.6), 261 (+18.2), 249 (+32.9); [α]20589= + 702 (c = 0.0264, CH2Cl2).
(+)-(RS ,P,R)-1,13-dimethoxy-5-methyl-9-propyl-13b-(((R)-p-tolylsulfinyl)methyl)-9,13b-dihydro-5H-quinolino[2,3,4-kl]acridine or (+)-(R, P4)-10n was synthesized according to general procedure D using 0.19 mmol (0.1 g) of rac-[DMQA][BF4] 1n. Least eluted fraction of P helicity. Second eluted fraction using achiral nucleosil column (Macherey Nagel, SP 250/10 Nucleosil 50-7) with
nhexane/iPrOH 90:10 as eluent (flow 3 mL/min, 23 °C, P = 39 bars, 200 μL per injection)) to afford 15.8 mg of P4 in 16 % yield.
1H-NMR (500 MHz, CDCl3) δ 7.27 (t, 3J = 10.0 Hz, 1H, H-C(11)), 7.09 (t, 3J = 10.0 Hz, 1H, H-C(3)), 7.01 (t, 3J = 10.0 Hz, 1H, H-C(7)), 6.99 (d, 3J = 10.0Hz, 2H, pTol(m)), 6.84 (d, 3J = 10.0 Hz, 2H, pTol(o)), 6.67 (d, 3J = 10.0 Hz, 1H, H-C(4)), 6.54 (d, 3J = 10.0 Hz, 1H, H-C(10)), 6.53 (d, 3J = 10.0 Hz, 1H, H-C(12)), 6.51 (d, 3J = 10.0 Hz, 1H, H-C(2)), 6.38 (d, 3J = 10.0 Hz, 1H, H-C(6)), 6.29 (d, 3J = 10.0 Hz, 1H, H-C(8)), 4.03 (d, J = 15.0 Hz, 1H, CH2SO), 3.97 (d, J = 15.0 Hz, 1H, CH2SO), 3.83 (s, 3H, OMe), 3.65-3.55 (m, 2H, NCH2CH2CH3), 3.35 (s, 3H, NMe), 3.35 (s, 3H, OMe), 2.31 (s, 3H, Me pTol), 1.82-1.70 (m, 2H, NCH2CH2CH3), 1.03 (t, 3J = 10.0 Hz, 3H, NCH2CH2CH3); 13C-NMR (125 MHz, CDCl3) δ 161.4 (C), 157.3 (C), 144.4 (C), 143.1 (C), 142.3 (C), 140.3 (C), 140.1 (C), 138.4 (C), 129.1 (CH, pTol), 128.9 (CH), 127.0 (CH), 126.4 (CH), 124.7 (CH, pTol), 116.8 (C), 110.9 (C), 110.7 (C), 106.7 (CH), 106.5 (CH), 105.5 (CH), 104.9 (CH), 104.2 (CH), 102.0 (CH), 67.5 (CH2, CH2SO), 56.1 (CH3), 55.2 (CH3), 48.9 (CH2,
148 | P a g e NCH2CH2CH3), 38.9 (C), 34.0 (CH3), 21.3 (CH3 pTol), 20.0 (CH2, NCH2CH2CH3), 11.0 (CH3, NCH2CH2CH3); IR 2958, 2875, 2833, 1586, 1476, 1436, 1386, 1343, 1243, 1226, 1178, 1169, 1145, 1126, 1090, 1058, 1037, 978, 951, 909, 811, 781, 733; UV/VIS (CH2Cl2, 2.1 x 10–5 M, λmax (log ε)) = 330 (4.07), 278 (4.10), 248 (4.43); CD (CH2Cl2, 2.1 x 10–5 M, 20 °C) λ (Δε) 328 (+40.0), 300 (+6.7), 277 (+32.7), 261 (+20.5), 248 (+42.1); [α]20589= + 662 (c = 0.023, CH2Cl2).
(–)-(M)-1,13-dimethoxy-5,9-dipropyl-5,9-dihydroquinolino[2,3,4-kl]acridin-13b-ylium 2,2,2-trifluoroacetate or (–)-[(M)-nPr-DMQA][PF6]: was obtained following the general procedure E starting from (–
)-(R,M)-10a, 90% yield:
)-(R,M)-10a, 90% yield: