1 Preamble

Whenever a chiral molecule demonstrates its utility in a certain field, its accessibility in enantiomerically pure form by a simple procedure, is often essential.

In this chapter, we will deal with several conjugated derivatives of triaryl methanes as seen in Figure II-1, in particular, the chiral dimethoxyquinacridinium (DMQA) salts 1.¹ Studies on the biological properties of DMQA structures will also be the focus of chapters III and IV.

Figure II-1: Chemical structure of the chiral DMQA salts 1 and other related derivatives 2-5

      

1 In chapter I, compounds 1, 2, 3, 4 and 5 were referred to as B39, B40, B38, B41 and B43 respectively.

22 | P a g e  II-2 Historical Background

Following the work of Laursen and Krebs,² on triazatriangulenium (TATA) salts 2 and their C2 -symmetric precursors DMQA salts 1, the Lacour’s group became interested in 2000, in the latter type of scaffolds, supposing that the repulsion of the terminal methoxy groups would force the molecule to adopt a helical conformation (Scheme II-1).

a: 2.5 eq. of amine R’NH2, NMP, RT, t = 20 h; b: 25 eq. of amine R’NH2, NMP, T = 110 °C, t = 1.5 h; c: ~50 eq. of amine R’NH2, NMP, T = 180 °C, t = 24 h.

Scheme II-1: Stepwise Nucleophilic Aromatic Substitution (SNAr) of methoxy groups of 6 by a primary amine leading to DMQA-1 and TATA-2 formation

In collaboration with Drs Laursen and Krebs from The Danish Polymer Centre, RISØ National Laboratory, Roskilde (Denmark), this was later confirmed by the X-ray structural analysis of samples of the tetrafluoroborate salt of the racemic dipropyl derivative rac-[(ⁿPr)2 -DMQA-1a][BPh4] as depicted in figure II-2.

  Figure II-2: General representation of the M and P enantiomers of helical DMQA with the X-ray crystal

structure for R = ⁿPr       

2 Laursen, B. W.; Krebs, F. C.; Nielsen, M. F.; Bechgaard, K.; Christensen, J. B.; Harrit, N. J. Am. Chem. Soc. 1998, 120, 12255-12263. Laursen, B. W.; Krebs, F. C. Angew. Chem. Int. Ed. 2000, 39, 3432-3434. Laursen, B. W. Ph.D.

Thesis, Univ. Copenhagen 2001, Ris∅-R-1275 (EN).

At that time, the majority of the [4]helicenes described in the literature, possessed essentially very low barriers of racemisation which prevented their resolution, we sought to verify if the same situation applied to this type of derivatives. To our greatest delight, these molecules presented extremely high configurational stability (ΔG^≠rac = 41.3 kcal/mol or 172.8 kJ/mol; t1/2

183 h at 200 °C)³ which promised the isolation of each of the possible enantiomers at RT and their manipulation without any of the drawbacks observed with most of their previous analogs (Chapter I, § I-5).

II-2.1.Previous Studies and resolution attempts

This new family of cationic [4]helicenes can be accessed through a simple two-step process (Scheme II-1, vide supra), albeit in racemic form. Their resolution is therefore essential to isolate the corresponding enantiomers.

This was sought at first, through the association of the cation with BINPHAT (BT) anion 7, a C2 -symmetric chiral hexacoordinated phosphorus derivative well established in our group.⁴ Since the cationic molecule is chiral and presents both M and P-conformers, this powerful enantiopure anion, permitted the formation of diastereomeric ion pairs with a high lipophilicity (Figure II-3).

O

Figure II-3: Chemical structure of Δ-BT (7) and Δ-TT (8)

      

3 values notably higher than the ones observed with [6]helicene (154.3 kJ/mol; t1/2 = 13.4 min at 196 °C).

4 Lacour, J.; Ginglinger, C.; Grivet, C.; Bernardinelli, G. Angew. Chem. Int. Eng. Ed. 1997, 36, 608-610; Lacour, J.;

Londez, A.; Goujon-Ginglinger, C.; Buß, V.; Bernardinelli, G. Org. Lett. 2000, 2, 4185-4188; Lacour, J.; Vial, L.;

Herse, C. Org. Lett. 2002, 4, 1351-1354; Pasquato, L.; Herse, C.; Lacour, J. Tetrahedron Lett. 2002, 43, 5517-5520;

Hebbe, V.; Londez, A.; Goujon-Ginglinger, C.; Meyer, F.; Uziel, J.; Jugé, S.; Lacour, J. Tetrahedron Lett. 2003, 44, 2467-2471.

24 | P a g e  Thus, a strong association was obtained between a solution of the cationic ⁿPr2-DMQA in dichloromethane or acetone and the enantiopure BINPHAT salt ([Me2NH2][(Δ,S)-7] or [Me2NH2][(Λ,R)-7] in acetone. After filtration on basic alumina of the 1:1 mixture of diastereomers, the separation of one of the ion pairs was possible through a careful selective precipitation, in THF/benzene (1:3 v/v), leaving the second one in the mother liquor in an enantioenriched form. By switching to the other enantiomer of BT, the second/opposite configuration of the cation can be isolated.

Scheme II-2: Resolution example of rac-ⁿPr2-DMQA 1a by association with (Δ, S)-7.

a) Resolution; b) ion metathesis with PF6 salts

As a general rule, association with the [Me2NH2][(Δ,S)-7] gives the [P-1][(Δ, S)-7] cation as an almost enantiopure precipitate (d.r. > 49:1). Its antipode is obtained thanks to the association with [Me2NH2][(Λ,R)-7] (Scheme II-2).⁵

Such a method based on solubility differences was deemed not applicable to all the derivatives and necessitated a large amount of solvents. It was therefore important to find an alternative more general and straightforward way.

      

5 Herse, C.; Bas, D.; Krebs, F. C.; Bürgi, T.; Weber, J.; Wesolowski, T.; Laursen, B. W.; Lacour, J. Angew. Chem.

Int. Ed. 2003, 42, 3162-3166.

II-2.2.Looking for a different approach

This was envisaged using the aptitude of these cationic derivatives to undergo a nucleophilic addition on their central carbon, affording neutral adducts that can then be separated through classical chromatography or HPLC.⁶

Scheme II-3: Nucleophilic addition on ⁿPr2-DMQA⁺ 1a

For instance, alkyl, aromatic and propargylic lithium and magnesium reagents add to rac-ⁿPr2 -DMQA 1a to form neutral moieties in very good yields (up to 95%).⁷

Other adducts of 1a were obtained in the group, for instance from the addition of the acetonitrile anion or from the dimethyl sulfone anion. Using the CHIRALPAK AD-H (Daicel) column with

nhexane/ⁱPrOH: 99/1 as eluent, a distinct separation between the two enantiomers was observed for the acetonitrile adduct. The subsequent isolation and analysis of these samples showed retention of configuration of the helicity, another proof of the configurational stability of these derivatives.

Switching from sulfone to an enantiopure sulfoxide, a new stereogenic center was added, giving access to two possible adducts from 1a. Our group settled on the (+)-R-methyl-p-tolyl sulfoxide       

6 Lofthagen, M.; Chadha, R.; Siegel, J. S. J. Amer. Chem. Soc. 1991, 113, 8785-8790.Lofthagen, M.; Clark, R. V.;

Baldridge, K. K.; Siegel, J. S. J. Org. Chem. 1992, 57, 61-69. Lofthagen, M.; Siegel, J. S.; Hackett, M. Tetrahedron 1995, 51, 6195-6208. Lofthagen, M.; Siegel, J. S. J. Org. Chem. 1995, 60, 2885-2890. Laursen, B. W.; Krebs, F. C.;

Nielsen, M. F.; Bechgaard, K.; Christensen, J. B.; Harrit, N. J. Am. Chem. Soc. 1998, 120, 12255-12263. Mobian, P.; Nicolas, C.; Francotte, E.; Bürgi, T.; Lacour, J. J. Amer. Chem. Soc. 2008, 130, 6507-6514. Baisch, B.; Raffa, D.;

Jung, U.; Magnussen, O. M.; Nicolas, C.; Lacour, J.; Kubitschke, J.; Herges, R. J. Amer. Chem. Soc. 2008, 131, 442-443. Guin, J.; Besnard, C.; Pattison, P.; Lacour, J. 2010 unpublished results.

7 Herse, C. Ph.D. Thesis, Univ. Geneva 2003, 3461 (FR).

26 | P a g e  9 which is easily accessible on a large scale by a 2-step synthesis as described for instance by Solladié et al.⁸

From there on, a new route to the resolution of DMQA derivatives was established and was optimized through the works of former group members Christelle Herse, Benoît Laleu and Pierre Mobian (Scheme II-4).⁹

Scheme II-4: First step of the resolution protocol of cationic [4]helicenes through enantiopure sulfoxide addition. Formation of diastereoisomers (–)-(R, M)-10 and (+)-(R, P)-10

Generally speaking, this protocol consisted of the in situ generation of the enantiopure sulfoxide anion from a fresh deprotonating solution of LDA, followed by a cannulation of the yellow anionic solution upon the suspension of the DMQA cation in THF, forming the new C-C bond which is detected by a loss of the colour in solution.

The regeneration of the cation under its enantiopure form was realized through a Pummerer fragmentation⁹ thanks to the high stability of these triaryl carbenium moieties that behave as exceptional electrofugal groups, better than a “proton”.^10,11

      

8 Solladie, G. Synthesis 1981, 185-196; Solladie, G.; Hutt, J.; Girardin, A. Synthesis 1987, 173.

9 Herse, C. Ph.D. Thesis, Univ. Geneva 2003, 3461 (FR); Laleu, B. Ph.D. Thesis, Univ. Geneva 2006, 3784 (EN);

Laleu, B.; Mobian, P.; Herse, C.; Laursen, B. W.; Hopfgartner, G.; Bernardinelli, G.; Lacour, J. Angew. Chem., Int.

Ed. 2005, 44, 1879-1883

10 This shall be detailed in section II-4 at the end of this chapter.

11 These derivatives are also regarded as super stable carbenium ions and their chemical stability is usually measured as a pKR+ value, a thermodynamical parameter defined as the affinity of the cation towards hydroxide anions, in other words its preferential existence in solution under the cationic form or as a carbinol.

Equation II-1: Definition of the pKR+ value (Hx = acidity function characteristic of the solvent system used and the carbenium ion/carbinol couple studied)

As shown above, the cationic derivatives 1 are then chiral, stable and fluorescent which makes them very interesting scaffolds. Absolute configuration for these compounds was determined thanks to a collaboration with Prof. Thomas Bürgi (ETHZ), Delphine Bas (UniGe), Tomasz Wesolowski (UniGe) and Jacques Weber (UniGe) which allowed the comparison of theoretical calculations of the VCD spectra with the experimental values, as well as the specific optical rotation signs.⁴

However, so far, only “lipophilic” derivatives had been prepared. To study their properties with biological targets, a need to make them water-soluble was identified and was one of the major objectives of my PhD. We considered that this could be obtained either by varying the side chains to make them more polar or by working on the nature of the counterion. This will be the subject of the next section.

II-3.Towards new water-soluble enantiopure dyes

II-3.1.Prologue

A charged molecule can form salts that should a priori be more soluble in water, at least as long as the side chains are short (C_n ≤ 3). When we started, the shortest side chain studied in our group for such molecules was n-propyl. However, methyl derivatives rac-Me2-DMQA⁺ 1b which had been described¹² ought to be considered for that matter.

On the other hand, a functionalization with free OH and NH2 groups was considered as it could give access to water-soluble compounds and as such, more bio-related derivatives.

II-3.2.Formation of the synthetic precursors

II-3.2.a. Synthesis of the polar rac-(OH (CH₂)₂)₂-DMQA⁺ 1c and rac-(NH₂ (CH₂)₂)₂ -DMQA⁺ 1d

For this purpose, commercially available ethanolamine and ethylenediamine were used and each amine reacted favourably with the tris(2,6-dimethoxyphenyl)carbenium ion 6, a dark violet material that is easily accessed in 20 to 30 gram-scale.²

       The higher the pKR+ the more stable is the cation. Accordingly, a value of 19.1 was obtained for the DMQA structures.

12 Laursen, B. W.; Krebs, F. C. Chem. Eur. J. 2001, 7, 1773-1783

28 | P a g e  These amines reacted without the need for protection¹³ of the second functional group or anhydrous conditions to give, after 1 h 30 at 110 °C in NMP, the desired products (rac-1c and 1d, Scheme II-5). The excess of amine and NMP was distilled under vacuo and the purification of the crude reaction mixtures required several washings with Et2O to remove unreacted acridinium intermediates. At this stage, further purification was obtained by solubilising the oily green material in a minimum of CH2Cl2 followed by the addition of an excess of Et2O to selectively precipitate the desired compounds in good to excellent yields (65-85%).

Scheme II-5: Synthesis of water-soluble rac-(OH (CH2)2)2-DMQA⁺ 1c and (NH2(CH2)2) 2-DMQA⁺ 1d

Having the racemic compounds in hand, their subsequent resolution necessitated first the protection of the polar groups (Equation II-2). In fact, the free alcohols of 1c present two acidic protons that could also be attacked by the enantiopure sulfoxide anion generated in situ and thus necessitate a higher number of equivalents of (+)-(R)-9 to afford the desired diastereoisomers 10.

  Equation II-2: Silyl protection conditions of the free alcohols for resolution 

      

13 No protection is needed for ethanolamine since the amino group reacts faster than the alcohol.

The free alcohol was therefore silylated with TBSCl, imidazole at 20 °C in DMF; this method was preferred to the one previously used in the group (TBSOTf / 2,6-lutidine),¹⁴ since the cheaper reagent allowed the same yield and purity (65%), without the need for distillation.

For the bis-amino derivative 1d, such a “latter protection” strategy was however not followed.

The extreme polarity of the adduct rendering its manipulation difficult, we went back to the step before and undertook the prior protection of the amine.

Ethylenediamine 11 therefore, reacted with di-tert-butyldicarbonate Boc2O in anhydrous dichloromethane to give boc-protected 12 in quantitative yield, according to the described protocol (Equation II-3).¹⁵

 

Equation II-3: Monoprotection of ethylenediamine 11 as tert-butyl-(2-aminoethyl)carbamate 12

The amino protected DMQA 1f was thus obtained in very good yield (75%) from tert-butyl (2-aminoethyl)carbamate 12 and carbenium ion 6 in the same previously described conditions (Equation II-4).

Equation II-4: Synthesis of the Boc-protected 1f

      

14 Laleu, B. Ph.D. Thesis, Univ. Geneva 2006, 3784 (EN). 

15 Jensen, K. B.; Braxmeier, T. M.; Demarcus, M.; Frey, J. G.; Kilburn, J. D. Chem. Eur. J. 2002, 8, 1300-1309.

30 | P a g e  II-3.2.b. Synthesis of a variety of other polar symmetrical dyes

At this stage, it was easy to apply these synthetic conditions to obtain a variety of other derivatives. Within the time limit, we opted for longer side chains because we considered that the free terminal amines in 1d, 1h-j could potentially react with another moiety of 6 to obtain dicationic species (see experimental part of chapter V). However, it was necessary that such chains be long enough not to have the possible repulsion generated by two proximate positive charges.

For that matter, two series of diamines (n = 2, 3, 4, 6; 1d and 1h-j) and aminoalcohols (n

= 2, 5; 1c and 1k) of varying lengths were formed (Scheme II-7, vide infra) with good to excellent yields (56-85%), except for 1i, due to purification problems.

Scheme II-7 Synthesis of symmetrical DMQA derivatives 1a-j with various side chain lengths 

II-3.2.c. X-Ray crystal structure analysis

To our satisfaction, a crystal structure of rac-(OH (CH2)2)2-DMQA⁺ 1c was obtained by selective recrystallisation of its tetrafluoroborate salt from a 1:1 mixture of n-hexane/methanol (Figure II-4). The structure was studied by X-Ray diffraction techniques, refined and analysed thanks to the expertise of Dr. G. Bernardinelli, from the crystallographic department of the University of Geneva (see Appendix A).

 

Figure II-4: X-Ray crystal structure representation of one of the two enantiomers of cation 1c obtained from the corresponding tetrafluoroborate salt of the racemic mixture. (Side view shown to the left to show

the helical twist and the top view to the right)

The crystalline system is monoclinical, with a space group defined as I 2/a. The structure is C2 -symmetric with the axis passing through the central carbon (special position 4e).¹⁶

The twist angle (or torsion / bending angle) between the two aromatic planes provoked by the repulsion between the two methoxy substituents on the ortho-positions, is calculated to be 38.5 °.

The interplanar distance in the system is a bit bigger compared to the one found in the dipropyl derivative 1a¹⁷(see § II-3.7.3).

No stacking is observed in the crystalline forming of the layers. Nevertheless, we can see that the molecules form columns parallel to the [100] direction in the figure, in a compacted pseudo hexagonal rearrangement (see Appendix A).

Another crystal structure was obtained for 1f and was suitable for X-ray diffraction studies. It presented data similar to the ones described for 1c and is shown in appendix B.

II-3.3.Resolution of rac-(TBSO (CH2)2)2-DMQA⁺ 1e through the “enantiopure sulfoxide addition” protocol

With these new protected structures in hand, we undertook the addition of the enantiopure sulfoxide at 0 °C using the same conditions shown previously.⁹

      

16 The anion BF4 is also on a C2-symmetric axis with both atoms B1 and F1 in a special position 4e, whereas the other fluorine atoms are dispersed in a random manner (see Appendix A).

17 Laursen, B. W. Ph. D. Thesis, Univ. Copenhagen 2001, RisØ-R-1275 (EN).

32 | P a g e  The TBS protected DMQA 1e underwent successfully the addition of the anion of (+)-(R)-9 to give a mixture of two diastereoisomers which were easily separated on silica gel (using Et2O/

Pentane 60:40 to 100:0 as eluent) in excellent yields (45% for (R, M)-10e and 49% for (R, P)-10e), thanks to a very large difference in their retention factors (ΔRf = 0.3-0.4; Figure II-5 vide infra).

Scheme II-8: Synthesis of the sulfoxide adducts from racemic DMQA 1e

Figure II-5: TLC plate of the crude mixture of the 2 diastereomers (left part) and superposition of the CD spectra (10^-5 M, CH₂Cl₂) of the most (a) and the least (b) eluted diastereomers of the sulfoxide derived

from symmetrical R’-DMQA⁺ cation (right part).

Furthermore, the ECD analysis of the isolated fractions confirmed that the first eluted fraction was the (R, M) diastereoisomer followed by the more polar (R, P) diastereoisomer, confirming what was already known for such compounds in the group. The derivatives 10e thus answered to the same rule (Figure II-5).

II-3.4.Formation of the DAOTA side products:

We noticed upon heating the TLC plates of the crude reaction mixture of the sulfoxide addition, the formation of a pink spot always at the top of the plate just before the most eluted of the two sulfoxide diastereoisomers (Figure II-5, vide supra). Furthermore, the medium is always slightly pink after the sulfoxide anion canulation on the DMQA cation to form the new C-C bond. This side product was identified by ¹H-NMR as the product of addition upon the DAOTA¹⁸ derivative.

This result i.e. the presence of DAOTA in the medium can be explained by two possibilities:

first, an initial contamination of the racemic DMQA sample albeit in an infinitely small amount that is not detected by ¹H-NMR can account for its presence. The other more probable explanation is an in situ demethylation reaction of one of the two methoxy groups due to the sulfoxide anion and consequent attack to form the ring closure by nucleophilic aromatic substitution SNAr (Figure II-6).

The slight excess of sulfoxide anion (0.5 equiv.) utilised for the reaction could then attack the DAOTA, affording the corresponding adduct.

Figure.II-6: Ring closure pathway to the planar DAOTA derivative through in situ demethylation by the nucleophile (sulfoxide anion).

II-3.5.Dealing with the amino protecting group: resolution of 1f

In the case of the protected rac-(BocNH (CH2)2)2-DMQA 1f, as expected, the use of 1.5 equivalents of the anionic resolving agent (+)-(R)-9 was not sufficient due to a probable deprotonation of the carbamate hydrogens. So, we undertook the resolution using 3 equivalents

      

18 DAOTA or diazaoxatriangulenium salt is a structural analogue of TATA with the third nitrogen being replaced by an oxygen atom, due to the activation of one of the methoxy substituents, making it a good leaving group.

34 | P a g e  of enantiopure sulfoxide 9. Unfortunately, the results were not as encouraging as the ones with the TBS group and only traces of adducts were obtained, not enough for the next steps.

We thought then about using a different protecting group which would leave no protons on the N-atom, such as the phthalimido group or even an azide.

Scheme II-9: Formation of the Phth-protected ethylenediamine as a hydrochloric salt 15

The synthesis of the Phthalimido protected ethylenediamine 14 proceeded in two steps.

First, it was necessary to protect one amine function with a boc group giving as described previously compound 12. Then the neat reaction between 1.1 equivalents of 12 and 1 equivalent of phthalic anhydride 13 at 130 °C¹⁹ for 1 h gave the doubly protected amine 14 after precipitation from methanol as a white solid in 60 % yield (Scheme II-9).

Compound 14 was then dissolved in ethanol at 25 °C and an excess of commercially available HCl.Et2O (1M in Et2O) was added dropwise to quantitavely afford 15 as a hydrochloric salt. This form necessitated of course the addition of triethylamine²⁰ to obtain the free amine in the subsequent reaction with 6.

However, the phthalimido group was apparently not such a good choice since after isolation of the corresponding acridinium, it was not possible, probably due to steric bulk,²¹ to form the second ring closure with the protected amine, even with increasing the temperature of the reaction up to 150 °C (Scheme II-10).

      

19 Tm of phthalic anhydride.

20 Potassium carbonate was also used but it wasn’t efficient for the formation of the free amine. Consequently, no reaction with 6 was observed qualitatively detected by the orange color of acridinium derivatives.

21 Even though electronic arguments are not overruled.

  Scheme II-10: Attempted synthesis of the Phth-protected DMQA 1k using 15

Another possibility was then sought, given that azido groups are also a form of amine

“synthon” that ought to be easily accessed and later reduced to afford the desired functional groups. We started from the high yielding DMQA-((CH2)2OH)2 1c, by rendering the diols better leaving groups through the formation of mesylates (CH3SO2Cl, Et3N, CH2Cl2, reflux, 73%) and then by their substitution with NaN3 (DMF, 24 h, 56%) (Scheme II-11).

 

Scheme II-11: Synthesis of the diazido DMQA 1m from the diol derivative 1b

The resolution of this new diazido cation 1m was then undertaken and using 1.5 equivalents of sulfoxide anion, the addition products were obtained, albeit in poor yields (13%

and 10% respectively for (-)-(R, M)-10m and (+)-(R, P)-10m). Unfortunately, even a gram-scale synthesis of 1m (800 mg to 1.5 g of starting DMQA-1m engaged in the sulfoxide addition reaction) did not afford higher yields of diastereomerically pure material due to the lower

36 | P a g e  conversion observed compared to the previous cases. This lack of reactivity is surprising and so far unexplained; possibly, the shorter chains were a perturbation.

To test this theory, we finally focused our attention on a longer derivative (n=5) in the terminal alcohol and azide series. This part will be detailed in chapter IV along with the synthesis and properties of derived structural analogues.

II-3.6.Case of the methyl derivatives: short side chain effects

II-3.6.a.Resolution of rac-(Me)₂-DMQA 1b

As mentioned, to form water soluble compounds, another possibility was the introduction

As mentioned, to form water soluble compounds, another possibility was the introduction

Dans le document Synthesis, resolution and biological applications of water-soluble Cationic [4]helicenes (Page 35-0)