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Practical isolation of the (1R,2R)-enantiomer from a racemic cis/trans mixture of 2-methyl-1-cyclohexanamine Markus Furegati, and Sandro Nocito Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00263 • Publication Date (Web): 04 Oct 2017 Downloaded from http://pubs.acs.org on October 4, 2017

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Organic Process Research & Development

Practical isolation of the (1R,2R)-enantiomer from a racemic cis/trans mixture of 2-methyl-1cyclohexanamine Markus Furegati,* Sandro Nocito Synthesis & Technologies Group, Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Klybeckstrasse 141, 4057 Basel, Switzerland KEYWORDS Crystallization, diastereomeric salt formation, salt screen, optical resolution

ABSTRACT

2-Methyl-1-cyclohexanamine exists in four stereoisomeric forms. Although it is a simple compound, none of the stereoisomers is readily available in its pure form. We herein described a crystallization method identified by a salt screen (diastereomeric salt formation) allowing the isolation of a single trans enantiomer from a readily available commercial source consisting of a mixture of all four stereoisomers.

INTRODUCTION

ACS Paragon Plus Environment

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More than 800 N-substituted compounds containing the 2-methyl-1-cyclohexanamine motif with distinct stereochemistry are described in the literaturea and many more without specification of the two stereocenters at the cyclohexane ring. We were surprised to find that sourcing of even 10 g of the enantiopure (1R,2R)-1 turned out to be difficult and reported syntheses thereof rather cumbersome and lengthy. In order to support our medicinal chemistry programs with this building block we were looking for an alternative approach. Seven syntheses to racemic or enantiopure trans-2-methyl-1-cyclohexanamine (1) and salts thereof are described in the literature starting from various precursors (Scheme 1). Scheme 1. Literature procedures (a-g) for the synthesis of racemic or enantiopure trans-2methyl-1-cyclohexanamine. See Scheme S1a-g in the SI for further details.

a SciFinder substructure search with substitution allowed only at the amine and relative trans stereochemistry revealed 581 compounds (search date June 30th 2017).


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The hydrogenation of N-(2-tolyl)acetamide (2) or anthranilic acid (3) gave direct access to racemic trans substituted cyclohexane cores that were further transformed to 1.1, 2 Hydroboration of 1-methylcyclohex-1-ene (4) was accomplished non-stereoselectively3, 4 or stereoselectively5, 6 and resulted after amination of the carbon-boron bond in the formation of 1; in the latter case (1S,2S)-1 HCl was obtained with 99% enantiomeric excess (ee) following a 5 steps sequence in 48% overall yield. Aziridination of cyclohexene (5) and subsequent ring opening led to (1R,2R)1 in 4 more steps.7 The shortest asymmetric synthesis is described as a 4 steps process starting from rac-2-methylcyclohexanone (6) yielding (1S,2S)-1 HCl salt in 5.6% and 92% ee.8 6 was also substrate for an enzymatic approach.9 The syntheses are discussed in more detail in the SI (Scheme S1). RESULTS AND DISCUSSION Despite the elegance of some of these approaches, we were aiming for a simple and quick access to (1R,2R)-1. Chiral amines were often efficiently resolved by diastereomeric salt formation with an enantiopure acid and liberation of the free amine from the salt.10 Depending on the selectivity additional crystallizations might be necessary in order to enrich enantiomeric excess. We found two literature precedents making use of this approach. The first one described the crystallization of rac 1 with D-camphorcarboxylic acid from hot EtOH/water. After recrystallization from dry ethanol two fractions were obtained of which the major one was recrystallized again several times (no yields given). The liberated free amine was assigned as the (– )-enantiomer.11 In the second one (+)-tartaric acid formed a 1:1 salt with (1S,2S)-1 (Scheme S1e).8 This single crystallization from methanol resulted in an increase of the enantiomeric excess from 70 to 92% with a yield of 28%; in other words, the minor (1R,2R)-enantiomer was depleted by a factor of 15.1 and the (1S,2S)-enantiomer by 3.6.


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We decided to submit racemic 1 to a salt screen and discovered that the pure racemic transisomer was not readily available from commercial sources. On the other hand, an isomeric mixture of racemic cis/trans-1 (between 1:4 and 3:7 for the batches we worked with) was offered by many vendors.b We used this mixture for the screen, hoping that alongside the resolution, removal of the undesired cis isomers would also be achieved in parallel. The screen consisted of 300 different resolving agent and solvent combinations. The 20 chiral acids have mostly been chosen based on widespread utilization, availability and price (Table 1 – see experimental section). Three of them were mixtures of a set of three similar chiral acids according to the Dutch resolution.12, 13

a)

b)

Figure 1. Heat maps of data from the salt screen (resolving agents A-T and solvents 1-15, see table 1) a) ee of trans-1, red: racemic, light green: maximum of 32%ee for G3 and N14 (both marked with red circles) b) content of trans-1, red: same composition as in starting material

b Catalogue price for 1 kg approximately 500 USD.


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(77% trans), green: accumulation, blue: depletion of trans enantiomers, the best result (L2) is marked with a red circle. Grey squares resulted in no crystal formation.

From the screen 44, crystalline salt samples were isolated with yields ranging from 18-64%. In order to determine the distribution of the stereoisomers the liberated amines from these salts were converted into the (S)-Mosher-amides and analyzed by GC with achiral stationary phase. Ee values from 0-44% were found for the cis isomers and 0-32% for the trans isomers (Figure 1a). Apart from sample L2 the cis/trans ratio was not at all or only slightly affected by the crystallization (Figure 1b). L2 showed in addition one of the best ee values of the screen, but only moderate yield: the diastereomeric salt formation with (R)-(−)-1,1’-binaphthyl-2,2’phosphoric acid ((R)-7) in EtOH/water 1:1 resulted in a significant depletion of the cis isomers in the isolated salt, while the ee of the trans enantiomers was increased to modest 26% (highest ee achieved was 32%) and a yield of 22%. A first scale-up with 6 g of 1 (1:4 cis/trans mixture) under those conditions resulted in a complete removal of the cis isomers after three subsequent crystallizations while the ee of the trans enantiomers increased to 79% with a yield of 20%. The resolvability S was calculated to be 0.40.c The absolute stereochemistry of the enriched trans enantiomer was determined as (1S,2S) by comparison of the optical rotation of its HCl salt [α]D21= +16.4 (c=4, MeOH) with the literature [α]D= −24.66 (c=4, MeOH) for the (1R,2R) enantiomer with an ee >99%.7 Next, the influence of a substoichiometric amount of the chiral acid was investigated. Because the amine was well soluble in the solvent mixture alone, no achiral strong acid was used to

c The resolvability also known as the Fogassy’s parameter was calculated as the product of the yield divided by the assay of the target isomer in the starting material (in this case 0.4) and the enantiomeric purity. S equals unity corresponds to complete separation.


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replace the more expensive chiral resolving agent as often applied by the Pope-Peachey method.10 0.1 mol 1 (3:7 cis/trans mixture, from a different vendor) was crystallized with 0.5 equivalents of (S)-7 in 250 mL EtOH/water 1:1. A single crystallization resulted in 26% yield (containing 3% of the cis isomers) and an ee of 39% (GC analysis of the (S)-Mosher-amides), resolvability S = 0.26.

Scheme 2. Diastereomeric salt formation, liberation of the amine and precipitation of the enantiopure (1R,2R)-1 as its HCl salt.

The main batch was performed on a 3.75 mol scale with a further reduced amount of the chiral acid (0.43 equiv.) Six consecutive crystallizations resulted in 73.2 g of the salt in 4.2% yield (Scheme 2) and an ee of 97.9% (GC analysis of the (S)-Mosher-amides) and 98.3% (HPLC of the tosylamide on a chiral stationary phase).d The overall resolvabilty S was calculated being 0.12. The transformation into the HCl salt was achieved by liberating the free amine and subsequent precipitation with HCl in diethyl ether in 92% yield.

d The latter value was more accurate, because the ee of the (S)-Mosher’s chloride used for the derivatization itself was only 99% according to the vendor and therefore resulted in a slight underestimation of the real ee of the amine


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Figure 2. Assay of the four stereo isomers of 1 in the commercial amine mixture (sm) and after each crystallization (1-6) , considering the material loss after each crystallization. Cis isomers were not detectable from the 2nd crystallization on. The cis isomers were completely removed after one single crystallization (Figure 2). Therefore, the initial cis/trans ratio of the starting material is expected to have a minimal influence on the total number of crystallizations required. When a stoichiometric amount of the resolving acid was used, three crystallizations were necessary for this, although the initial cis/trans ratio was in favor for the trans isomer. The resolution of the trans enantiomers was less efficient, the average depletion factor of the undesired diastereomeric salt was 3.1 and that of the target salt 1.5. In other words, after each crystallization 30% of the target enantiomer went lost, while the ratio of the undesired to the desired enantiomer improved by a factor 2.2. CONCLUSIONS


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The method we described allows the isolation of enantiomerically pure trans-2-methyl-1cyclohexanamine (1) from a commercial mixture of racemic cis/trans isomers via diastereomeric salt formation with 1,1`-binaphthyl-2,2`-phosphoric acid (7), available in both enantiomeric forms, in environmentally benign water/ethanol solvent. Despite the low overall yield and the six consecutive crystallizations necessary to exceed an ee of 98%, this route represents in our view the most practical way to access enantiopure trans-1 to date for lab scale. For large scale however, a process based on a simple racemic process followed by efficient SMB chromatography (similar to Scheme S1a) or an asymmetric transfer hydrogenation (Scheme S1e) should be considered. EXPERIMENTAL SECTION General. All reagents were purchased and used as received unless otherwise noted. 2-Methyl-1cyclohexanamine from TCI, (S)-(+)-1,1`-binaphthyl-2,2`-phosphoric acid from A Chemtek Inc., (S)-(+)-α-methoxy-α-trifluoromethylphenylacetyl chloride (Mosher’s chloride from Sigma Aldrich. LC-MS method: Acquity HSS T3 1.8 um 2.1 x 50 mm column at 50 °C. Eluent A: water + 0.05% formic acid + 3.75 mM ammonium acetate; eluent B: acetonitrile + 0.04% formic acid; gradient: from 2 to 98% B in 1.4 min with a flow rate of 1.2 mL/min, detection at 210-450 nm. HPLC method:7 Chiralpak AD-H (250x4.6 mm, 5 um) column, heptanes/EtOH 70:30, column temperature r.t., flow rate 1 mL/min, detection at 230 nm, run time 17 min. Purities were characterized with area% at the wave length declared for the method used. GC method (for indirect ee determination): Silaren column (30 m x 0.32 mm ID, 0.12 µm film). Temperature program: 40°C held for 0.3 min, followed by 3.5 °C/min up to 200 °C and 40 °C/min up to 280 °C, at which the temperature was held for 3 min. The hydrogen flow was 2 mL/min, the front inlet temperature was 220 °C, and the front detection (FID) temperature was 300 °C; split ratio


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1:50. NMR spectra were recorded on a Bruker BioSpin machine. 1H shifts were referenced to DMSO-d6 at 2.49 ppm and CDCl3 at 7.26 ppm. 13C shifts were referenced to DMSO-d6 at 39.52 ppm. Optical rotations were measured on a Perkin Elmer 241 Polarimeter. Determination of the enantiomeric excess Mosher-amide method: ca 2-3 mg of the salt were extracted with 1 ml DCM and 0.6 ml sat. NaHCO3 solution. The DCM phase was filtered through a 2 cm plug of sodium sulfate contained in a disposable glass pipette into a GC vial. 10 µL diisopropylethylamine and 5 µL (S)-(+)-αmethoxy-α-(trifluoromethyl)phenylacetyl chloride (Mosher`s chloride) were added and after standing for 30 min the sample was submitted for GC analysis: tR (cis-enantiomer 1) = 43.99 min, tR (cis-enantiomer 2) = 44.15 min, tR (1S,2S-enantiomer) = 44.70 min, tR (1R,2Renantiomer) = 45.03 min. Tosylamide method: to a suspension of 1-HCl (100 mg, 0.67 mmol) in DCM (4 mL) was added at r.t. triethylamine (0.28 mL, 2.01 mmol) and TsCl (127 mg, 0.67 mmol). The resulting reaction mixture was stirred for 1 h. The reaction mixture was successively washed with sat. sodium bicarbonate solution (10 mL), 0.1 N HCl (10 mL), sat. sodium bicarbonate solution (10 mL) and brine (10 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo at 45°C to yield 186 mg (quant.) of 4-methyl-N-(2-methylcyclohexyl)benzenesulfonamide (8) as a colorless oil that crystallized after a few minutes at r.t.14 LC-MS: tR = 1.17 min (97.7a%); m/z 268 [M+H]+. HPLC: tR (1R,2R-enantiomer) = 7.55 min, tR (1S,2S-enantiomer) = 10.45 min.7 Salt screen


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300 combinations consisting of 20 chiral acids and 15 solvents or solvent mixtures were applied (Table 1). The choice of chiral acids and solvents was inspired by the ‘CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation’.10 Table 1. Resolving agents and solvents used for the screen (300 combinations).

A

L-(+)-tartaric

acid

1

water

B

(–) O,O’-diacetyl-L-tartaric acid

2

EtOH/water 50:50

C

(+)-O,O’-dibenzoyl-D-tartaric acid

3

EtOH/water 96:4

D

(+)-O,O’-di-(4-toluoyl)-D-tartaric acid

4

EtOH abs.

E

(R)-(–)-mandelic acid

5

MeOH

F

(S)-(–)-malic acid

6

2-PrOH

G

N-acetyl-L-leucine

7

acetone

H

N-acetyl-L-phenylalanine

8

2-butanone

I

N-acetyl-L-valine

9

EtOAc

J

(1S)-(+)-10-camphorsulphonic acid

10

EtOAc + 2.5vol% water

K

(1R,3S)-(+)-camphoric acid

11

acetone/CHCl3 1:1

L

(R)-(-)-1,1’-binaphthyl-2,2’-phosphoric acid

12

acetonitrile + 2.5vol% water

M

D-(–)-quinic

13

MeOH/water 2:1

N

(+)-deoxycholic acid

14

EtOAc/EtOH 1:1 + 4vol% water

O

L-pyroglutamic

15

TBME + 1vol% water

P

(1S)-(+)-3-bromocamphor-10-sulfonic acid mono hydrate

Q

(+)-3-bromocamphor-8-sulphonic acid

acid

acid


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R

P-Mix, consisting of a 1:1:1 mixture of (S)-(+)phencyphos hydrate, (R)-(+)-anicyphos and (R)(+)-chlocyphos

S

M-Mix, consisting of a 1:1:1 mixture of (R)-(–)mandelic acid, (R)-(–)-4-methyl mandelic acid, (R)-4-bromo mandelic acid

T

T-Mix, consisting of a 1:1:1 mixture of (+)-O,O’dibenzoyl-D-tartaric acid, (+)-O,O’-di-(4-toluoyl)D-tartaric acid, D-(+)-dianisoyl-tartaric acid

For each combination 0.05 mmol racemic cis/trans mixture of 1 and a stoichiometric amount of a chiral acid were used in a concentration range starting from maximum 250 mM (200 µL) down to 25 mM (2 mL). 500 µL of a freshly prepared solution (100 mM) of 1 (cis/trans ratio of 23:77) in MeOH and 625 µL of freshly prepared solutions (80 mM) of the chiral acids in MeOH, DCM or 1:1 mixture thereof were distributed into 300 2 mL HPLC vials arranged on an aluminum plate. After removal of the solvent in vacuo at 30°C the 15 different solvents were added and the vials closed with a screw cap. After heating at 80°C in a drying oven for 1-2 h (occasional manual shaking) the vials containing clear solutions were placed on a second, identical plate and allowed to cool to r.t. To the remaining vials were added solvents in 0.2 to 0.5 mL portions and the heating and selection steps repeated until the vials were full (1.8 mL). After one day in 39 vials crystals were found that were separated from the mother liquor either by filtration or decantation followed by drying with paper towel. The crystals were not washed, eventually the mother liquor was used to transfer the crystals that were further dried in vacuo at 40°C. In a second round the vials were stored at 4°C for a week and another 5 crystalline salts collected. The yields were calculated based on the weight assuming a 1:1 stoichiometry and the ee determined by the Mosher-amide method.


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(1R,2R)- 2-methyl-1-cyclohexylammonium (S)-(+)-1,1'-binaphthyl-2,2'-phosphate. 1st crystallization 2-methyl-1-cyclohexanamine (1) with a cis/trans ratio of 30:70 (493 ml, 3.75 mol) was dissolved in EtOH/water 1:1 (6 L) and loaded into a 10 L triple jacketed reactor (AMSI-Glas) with automated temperature control and equipped with an Unistat 385W cooling/heating unit, reflux condenser and nitrogen inlet. To the yellow solution (S)-(+)-1,1`binaphthyl-2,2`-phosphoric acid (7) (561 g, 1.61 mol, 0.43 equiv.) was added. The temperature raised from 22°C to 50°C, the pale brown suspension was heated to reflux (85°C internal temperature, jacket temperature was set to 100°C. Further EtOH/water 1:1 (0.5 L) was slowly added until all solid parts went into solution. The clear pale brown solution was allowed to cool to 20°C internal temperature over a period of 3 h and stirred for another 2 h at 20°C. The crystals were filtered off and dry-sucked thoroughly (no washing). The solid was dried in vacuo at 50°C until constant weight was obtained (overnight). 391.5 g (yield: 22.4%) of crop-1 in form of colorless crystals were obtained. GC analysis of the Mosher-amides revealed an ee of 36.9% (containing 2% of the cis isomers). 2nd crystallization Crop-1 (391.5 g) was combined with a trial batch (11.9 g) of similar composition (ee= 38.7%, 3% cis-isomers) and suspended in EtOH/water 1:1 (6 L). The pale brown suspension was heated to reflux (85°C internal temperature, jacket temperature was set to 100°C). Further EtOH/water 1:1 (2 L) was slowly added until all solid parts went into solution. The clear colorless solution was allowed to cool to 20°C internal temperature over a period of 3 h and stirred for another 2 h at 20°C. The crystals was filtered off and dry-sucked thoroughly (no washing). The solid was dried in vacuo at 50°C until constant weight was obtained (overnight). 268.2 g (yield: 15.4%) of crop-2 as colorless crystals were obtained. GC analysis of the Mosheramides revealed an ee of 62.9% (no cis isomers detectable).


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3rd crystallization Crop-2 (268 g) was suspended in EtOH/water 1:1 (6 L + 1.3 L slowly added when hot). The exact same procedure was applied as described under the 2nd crystallization. 189.7 g (yield: 10.9%) of crop-3 as colorless crystals were obtained. GC analysis of the Mosheramides revealed an ee of 82.0%. 4th crystallization Crop-3 (189.7 g) was suspended in EtOH/water 1:1 (4 L + 1.5 L slowly added when hot). The exact same procedure was applied as described under the 2nd crystallization. 139.4 g (yield: 8.0%) of crop-4 as colorless crystals were obtained. GC analysis of the Mosheramides revealed an ee of 91.9%. 5th crystallization Crop-4 (139.4 g) was suspended in EtOH/water 1:1 (3 L + 1.8 L slowly added when hot). The exact same procedure was applied as described under the 2nd crystallization apart from the washing of the product. This time the filtercake was washed twice with ice cold (18°C) ethanol / water 1:1 (2x 300 ml) before drying. 96.7 g (yield: 5.6%) of crop-5 as colorless crystals were obtained. GC analysis of the Mosher-amides revealed an ee of 96%. Due to the large loss in the washing process the washing liquid was added to the next crystallization. 6th crystallization Crop-5 (96.7 g) and the washing liquid (0.7 L) were suspended in EtOH/water 1:1 (1.8 L + 1.8 L slowly added when hot). The exact same procedure was applied as described under the 2nd crystallization. 73.2 g (yield: 4.2%) of crop-6 as olorless crystals were obtained. GC analysis of the Mosher-amides revealed an ee of 97.9%. 1H NMR (600 MHz, DMSO-d6) δ 8.05 (dd, J = 18.5, 8.5 Hz, 4H), 7.88 (s, 3H), 7.51 – 7.39 (m, 4H), 7.31 (ddd, J = 8.1, 6.6, 1.3 Hz, 2H), 7.22 (d, J = 8.5 Hz, 2H), 2.45 (td, J = 10.8, 3.8 Hz, 1H), 1.83 (dt, J = 13.3, 3.4 Hz, 1H), 1.57 (dq, J = 12.7, 2.9 Hz, 1H), 1.52 – 1.43 (m, 2H), 1.32 – 1.22 (m, 1H), 1.21 – 1.05 (m, 2H), 1.00 (dddd, J = 15.6, 12.3, 8.2, 3.6 Hz, 1H), 0.86 – 0.82 (m, 1H), 0.84 (d, J = 6.5 Hz, 3H).


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(1R,2R)-2-methyl-1-cyclohexanamine hydrochloride ((−)-(1R,2R)-1-HCl). Crop-6 (72 g, 156 mmol) was suspended in TBME (500 ml) and ice water (500 ml). Sodium hydroxide solution 1M in water (187 ml, 187 mmol) was added within 5 minutes. The resulting biphasic mixture was stirred for 5 min at room temperature. After phase separation, the aqueous layer was washed four times with TBME (4 x 300 ml). During this procedure, phosphoric acid sodium salt precipitated that was filtered off (glass fritt, good filtration). The organic phase was washed twice with brine (2 x 300 ml) and dried over sodium sulfate, filtered and concentrated in vacuo at 40°C/180 mbar to a volume of ca 500 ml, the clear solution became slightly turbid after standing at r.t. and was filtered through a hard paper filter. To this clear and colorless solution was added under argon and vigorous stirring a solution of hydrochloric acid 1M in diethyl ether (156 ml, 156 mmol) dropwise within 30 minutes until pH 1 (25 ml of HCl solution were left). A white suspension was formed that was stirred for another hour at room temperature. The product was filtered off and the solid was washed three times with diethyl ether. The solid was dried in vacuo at 45°C until constant weight was obtained. 21.4 g (−)-(1R,2R)-1-HCl (92% yield) as white crystals were obtained. The overall yield of the resolution was 3.9% based on the racemic isomeric mixture of 2-methyl-1-cyclohexanamine that allowed a maximum theoretical yield of 35% (½ of the 70% trans isomers). ee= 98.3% (tosylamide method). 1H-NMR (400 MHz, DMSO-d6) δ 8.03 (s, 3H), 2.58 (td, J = 10.6, 4.0 Hz, 1H), 2.01 – 1.92 (m, 1H), 1.73 – 1.62 (m, 2H), 1.62 – 1.53 (m, 1H), 1.53 – 1.38 (m, 1H), 1.31 – 1.06 (m, 3H), 1.06 – 0.96 (m, 1H), 0.94 (d, J = 6.5 Hz, 3H). Optical rotation: [α]D22 –24.7 (c=4.0, MeOH) confirmed the correct enantiomer.7 ASSOCIATED CONTENT


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Supporting Information. A pdf summarizing the current literature approaches toward 1. AUTHOR INFORMATION * To whom correspondence should be addressed. Tel: +41 61 6964576. E-mail: [email protected]. ACKNOWLEDGMENT The authors would like to thank Caroline Radoch for analytical support. REFERENCES 1. 2.

3.

4. 5.

6.

7.

8.

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10.

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