resolutions with families of resolving agentsit turns out that strongly acidic resolving agents,...

University of Groningen

Resolutions with families of resolving agentsNieuwenhuijzen, Josina Wilhelmina

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Citation for published version (APA):Nieuwenhuijzen, J. W. (2002). Resolutions with families of resolving agents: principles and practice.[Groningen]: [s.n.].

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Chapter 3*

Benzylidene camphor sulphonates and 1-phenylethane sulphonic acids: possible new families of resolving agents In this Chapter two families of chiral sulphonic acids are described. The first group constitutes the benzylidene camphor sulphonates which are derived from camphor sulphonic acid. The synthesis of these compounds and derivatives is discussed, together with attempted resolutions. The second group of compounds comprises 1-phenylethane sulphonic acids. A new synthetic route to these materials is described, as well as some resolution experiments.

* Vries, T.R., Nieuwenhuijzen, J.W.; Pouwer, K.; Kellogg, R.M.; Kaptein, B.; Hulshof, L.A.; Broxterman, Q.B. Synthesis 2002, manuscript in preparation

Chapter 3

48

3.1 Introduction

Camphor sulphonic acid 3.1 and bromocamphor sulphonic acid 3.2 are well known resolving agents in industry, of which camphor sulphonic acid 3.1 is probably most used (Figure 3.1).1,2 The absolute configurations are those indicated; owing to the fact that both derive from natural sources only the indicated enantiomers are easily obtainable.

Figure 3.1 Known chiral sulphonic acids

1-Phenylethane sulphonic acid 3.3 (1-PES) also has been recognized as a resolving agent, particularly for the resolution of amino acids, but not used on large scale.3 These materials are strongly acidic, which can be advantageous in resolving weakly basic amines. Camphor sulphonic acids are also widely used for the resolution of amino acids.2,4 The camphor skeleton itself has been frequently applied as building block for chiral auxiliaries.5

Recently, amino acids have become increasingly important in the pharmaceutical industry, e.g. in peptide analogues and β-lactam antibiotics. The natural L-amino acids are usually readily available, contrary to the D-amino acids. One of the methods to obtain D-amino acids is via optical resolution of the corresponding synthetic racemic amino acid. Since amino acids occur as zwitterions, it is not possible to resolve them with weakly basic or weakly acidic resolving agents. It turns out that strongly acidic resolving agents, such as sulphonic acids, are suitable for the resolution of amino acids.2 Apart from the ones shown in Figure 3.1, there are few chiral sulphonic acids known.

The excellent resolving ability of camphor sulphonic acid is attributed to the combination of two structural features: the flexible hydrophilic methylene sulphonic acid site and the rigid hydrophobic camphor skeleton.6 The crystal structures of both diastereomers in the resolution of DL-phenylglycine 3.4 with 3.1 have been determined and thoroughly investigated.6

In the less-soluble diastereomer, densely packed alternating layers are formed consisting of either phenylglycine or camphor sulphonate. The more-soluble salt has a less dense structure with unoccupied spheres (holes), which fact could explain the higher solubility.

OSO3H

O

Br

HO3S

SO3H

1-PES3.33.1 3.2

H2NOH

O

3.4

Benzylidene camphor sulphonates and 1-phenylethane sulphonic acids: possible new families of resolving agents

49

At DSM in Venlo, the resolution of DL-phenylglycine 3.4 with 3.1 has been performed on large scale. D-Phenylglycine 3.5 is an important raw material for the preparation of penicillin (Box 3.1).7,8 p-Hydroxyphenylglycine 3.6, which is also employed for this purpose, cannot be resolved by 3.1 due to poor crystallization characteristics of the less-soluble diastereomer.9 However, bromocamphor sulphonic acid 3.2 is effective for this resolution.10 Apparently the p-hydroxy group plays an important role in the formation of the crystal lattice,6 probably by formation of an extra hydrogen bond.9

In our search for new resolving agents, we describe in this Chapter the derivatization of camphor sulphonic acid 3.1 with (substituted) benzaldehydes 3.7 (Scheme 3.1). A family of resolving agents for Dutch Resolution (see Section 2.5) would potentially be available, simply by using widely available substituted benzaldehydes. Moreover, we describe the development of a new synthetic route towards 1-phenylethane sulphonic acid 3.3, which is also applicable for synthesis on a larger scale. Two new sulphonic acids are described and these form, together with 3.3, a new family of resolving agents that might find its application in Dutch Resolution.

3.2 Synthesis of benzylidene camphor sulphonates

The condensation of camphor sulphonic acid 3.1 with p-substituted benzaldehydes 3.7 in the presence of sodium methoxide has been described in several patents.11 The reaction proceeds smoothly and the products 3.8 precipitate from the reaction mixture after addition of water. The benzylidene camphor sulphonates 3.8 are very crystalline and form beautiful colourless flakes upon recrystallization from water. The yields are in the range of 12-73% after recrystallization and reactions were typically performed on a 0.12 mol scale.

The sulphonates can also be prepared from the potassium camphor sulphonate 3.9 and the aldehydes 3.7 in DMSO with KOH as a base furnishing the corresponding potassium benzylidene camphor sulphonates 3.10. However, it is difficult to get rid of all the solvent DMSO during work-up and this procedure needs an additional step, namely the synthesis of 3.9 from camphor sulphonic acid 3.1. Therefore, the procedure with sodium methoxide is preferred.

Box 3.1 Resolution of phenylglycine(Phg) with camphor sulphonic acid(CSA) at DSM Fine Chemicals The manufacture of D-phenylglycine3.5 via resolution with camphorsulphonic acid 3.1 is performed inaqueous medium. The resolution itselfis very efficient, with above 40% yield(50% max.) and >95% ee (S≥0.76)The unwanted L-isomer is racemizedin a separate step and the resolvingagent can be recycled, which makesthe process extremely cost-effective.

H2NOH

O

D-Phg 3.5

Chapter 3

50

Scheme 3.1 Synthesis of benzylidene camphor sulphonates 3.8 and 3.10

The benzylidene camphor sulphonates that are formed have been patented as additives in sunscreens, in view of their characteristic UV-properties (Box 3.2).11

Box 3.2 UV-properties of benzylidenecamphor sulphonates

The figure shows the transmission (100% isfully transparent) of some camphorbenzylidene sulphonates. Sunburn(erythema) results from excessive exposureof the skin to rays of the sun withwavelengths in the range of 280-315 nm.However, a suntan is obtained withwavelengths of 315-400 nm. Among otherproperties, an effective sunscreen filters theshorter wavelengths of the erythmatous zone.

O

X

SO3Na

OSO3H

X

H

O

3.8a X=H3.8b X=Me3.8c X=OMe

NaOMe, Toluene, ∆

3.7a X=H3.7b X=Me3.7c X=OMe3.1

OSO3K

X

H

O


DMSO, KOH

O

X

SO3K


3.9

KOH


51

Theoretically, E and Z isomers can be formed in the condensation reaction described above. The 1H-NMR spectrum shows only one set of peaks. COESY-NMR of 3.8c allows assignment of all the protons (Figure 3.2). It shows a coupling between the CH-proton of the double bond (nr. 8) around 7 ppm with the bridgehead CH (nr. 6) at 2.8 ppm.

O

MeO

SO3Na

HH

3.8c

12

3

4

56

7

8

9

10

Figure 3.2 COESY-NMR of 3.8c

1

2

34

65

7

9

8

10

Chapter 3

52

In the NOESY spectrum, a clear NOE-effect is observed between an aromatic proton (presumably H9) and the bridgehead proton H6 (Figure 3.3) and not between H8 and H6, so the configuration around the benzylidene double bond was assigned as E.

Figure 3.3 NOESY of 3.8c

O

MeO

SO3Na

HH

3.8c

12

3

4

56

7

8

9

10


53

It is assumed without further proof that all condensation products have E stereochemistry around the double bond.

3.3 Attempted resolutions with the benzylidene camphor sulphonates

To the best of our knowledge, the use of benzylidene camphor sulphonates as resolving agents has not been reported in the literature. We attempted several resolutions with these materials. The racemic substrates that were tested are displayed in Figure 3.4. In several cases a crystalline precipitate was obtained, but this turned out to be the benzylidene camphor sulphonate itself. Apparently crystalline salts do not form.

Figure 3.4 Racemates tested in resolutions with benzylidene camphor sulphonates

The attempted resolutions were performed in several solvents, such as 10% HCl, pure or combined with MeOH, EtOH or iPrOH, but this procedure did not result in the desired salt formation.

H2NOH

OH2N

OH

O

OH

NH2

OH

O

X

NH2OH

p-hydroxy-PhgcyclohexylglycineX = H, OMe

β-aminophenylpropionic acid phenylglycinol

OH

HN

NH2

X

ephedrineX = Cl, Br, Me

phenylethylamine

H2NOH

OH2N

OH

O

OH

Tyr

H2NOH

O

SH

Cys

H2NOH

O

OH

SerPhg

Chapter 3

54

The corresponding sulphonic acids were obtained by passing the sulphonates 3.8 over an Amberlite IR-120 column. The use of the free sulphonic acids instead of the sulphonates 3.8 did not lead to the desired salts.

The introduction of the benzylidene substituent on the camphor skeleton perhaps prevents the formation of a layered structure dense enough to crystallize. The introduction of a hydrophobic group causes a change in dipole moment which could be unfavorable for salt formation. The crystallization of the benzylidene camphor sulphonates is apparently energetically more favorable than the crystallization of a salt.

3.4 Synthesis of benzyl camphor sulphonates

The introduction of a rigid double bond in the molecule could be the cause of the lack of salt formation with the benzylidene camphor sulphonates. Introduction of more flexibility might help. Therefore, the benzyl camphor sulphonates 3.11 were synthesized via hydrogenation of the benzylidene camphor sulphonates 3.8 at 1 bar (Scheme 3.2).

Scheme 3.2 Synthesis of benzyl camphor sulphonates 3.11

In this case two diastereomers are formed, which can be epimerized to a thermodynamically determined mixture of exo and endo diastereomers under basic conditions and crystallized from water. The endo: exo ratio can be determined by 1H-NMR (see also Section 3.10) We do not have definite proof for the absolute configuration of the newly formed chiral center.

H2

O

X

SO3NaO

X

SO3Na


Pd/C. 1 bar



55

3.5 Attempted resolutions with the benzyl camphor sulphonates

Benzyl camphor sulphonates have not been described in literature to the best of our knowledge. As a result, no resolutions have ever been performed. We tried the same set of racemic substrates as shown in Figure 3.4, under various conditions. Unfortunately, no crystalline salts were obtained. Contrary to the benzylidene camphor sulphonates 3.8, no precipitation occurred at all. Also, the use of the free sulphonic acid did not lead to precipitation of the desired salts.

Even the introduction of a more flexible side chain to the camphor skeleton did not result in salt formation. If a layered structure is needed for a salt to form, apparently this is still not possible even after hydrogenation of the double bond.

3.6 A new synthetic route for the preparation of 1-PES 3.3

1-Phenylethane sulphonic acid 3.3 has been known for more than 100 years. Evans et al. described the substitution reaction of 1-phenylethane chloride 3.12 with sodium sulphite in water,12 giving the sulphonate 3.13 (Scheme 3.3).

This method was later used by others13 and relies on the precipitation of the product 3.13 from the reaction mixture. However, in our hands, this procedure failed.14 The precipitation of 3.13 turned out to be difficult and the isolation of the product without any salts left was impossible.

Scheme 3.3 Synthesis of 3.13 via substitution of 1-phenylethane chloride 3.12 with Na2SO3

Another method that was described in literature comprises the addition of sodium bisulfite to styrene 3.14 (Scheme 3.4).15

Scheme 3.4 Addition of sodium bisulfite to styrene 3.14

Cl SO3NaNa2SO3

3.12 3.13

SO3Na

3.13

NaHSO3

3.14

+SO3Na

3.15

Chapter 3

56

In the early 1930s, it was believed that the desired asymmetric product 3.13 was formed, but later on it turned out to be largely the linear sulphonate 3.15,16 which is of course not suitable for our purposes. These results were reproduced by us.14 In fact, Miller described already in 187717 that this reaction should be possible, but he could not perform it, since “Die Frage, ob sich das Sulfoxylradical an das dem Phenylradical benachbarte oder entfernter liegenden Kohlenstoffatom angelagert hat (…) konnte wegen der schweren Beschaffung von Untersuchungsmaterial bis jetzt nicht entschieden werden.”

An enantioselective route to enantiomerically pure 3.3 was described by Corey in 1992 (Scheme 3.5).18 In this route, acetophenone 3.16 is reduced under the influence of a chiral oxazaborolidine catalyst 3.1719 and the corresponding alcohol 3.18 is obtained in 96% ee and 99% yield. This is a highly elegant procedure to obtain enantiomerically pure 3.18, but for larger scale applications the catalyst is relatively expensive.20 Moreover, another three steps need to be performed with enantiomerically pure material and this bears some risk. If 3.3 is prepared in racemic form and subsequently resolved, this problem is circumvented and both enantiomers of the acid are available in a single resolution procedure.

Scheme 3.5 Enantioselective route to 3.3 according to Corey

The second step is a Mitsunobu reaction to introduce the thioacetate 3.19. This is a rather costly method to introduce a sulfur functionality and it most likely involves column chromatography to remove the triphenylphosphine oxide that is formed during the reaction. Therefore, also this step is not suitable to use on a larger scale. The thioacetate is subsequently reduced to the thiol 3.20 via a standard LiAlH4-reduction in ether.

Other methods to oxidize thiol 3.20 to the corresponding acid 3.3 are known in literature, for instance the use of KMnO4

21 or more recently, a silver peroxodisulfate.22 Since the product is

water soluble, the work-up procedure is quite difficult. In our hands, it was almost impossible

CH3

O

3.16

N BO

Bu

PhPhH

10 mol% 3.17

BH3.THF

CH3

HO H

3.1896% ee

CH3

H S

O

CH3PPh3

(iPrOCON)2

CH3COSHTHF

LiAlH4

Et2O

CH3

H SH30% H2O2

CH3CO2H

CH3

H SO3H

3.19

3.20 3.3


57

to obtain pure sulphonic acid 3.3 without remaining salts using KMnO4 as oxidant. Also, oxidation with ozone is known,23 but this also failed in our hands.

Another possibility could be to oxidize the thiol to the corresponding sulphonyl chloride with Cl2-gas.24 However, this procedure is known to be dangerous and it also did not seem suitable for use on larger scale.

Considering all the above, we wanted to develop a route to enantiomerically pure 1-phenylethane sulphonic acids 3.3 that is easy to perform on larger scale, reliable and uses relatively cheap starting materials. The method should also be suitable for substituted 1-phenylethane sulphonic acids, so that a new family of resolving agents can be developed.

We synthesized 1-phenylethyl alcohol 3.18 via a standard NaBH4-reduction of the corresponding acetophenone 3.16 (Scheme 3.6).

Scheme 3.6 A new synthetic route for the preparation of 3.3

Subsequently, the alcohol needed to be converted to a thiol or a sulfur-containing functionality that can be converted to the sulphonic acid in the end. We chose to use the thiourea salt 3.21 that can be easily prepared in high yield via a reaction of 3.18 with thiourea in the presence of HBr. The alcohol is in situ converted to the bromide, which subsequently reacts to the thiourea salt 3.21. In theory it should be possible to convert the thiourea salt directly to 3.3, but since we had encountered problems in purification before, we decided to hydrolyze 3.21 to the thiol 3.20 and use this in the oxidation reaction (see Table 3.1). A disadvantage is obviously the smell of 3.20, which can be a problem on larger scale.

The p-methoxy substituted thiol could be obtained in a very low yield from the corresponding alcohol. A large amount of polymeric material was formed in this reaction, which is most likely to be polystyrene, from styrene that is formed upon elimination of H2S from the thiol. Therefore, methoxy substituted 3.3 was not accessible.

CH3

O OH Br

SO3H

NaBH4

S

NH2H2N

10% NaOHAcOH

SH

EtOHS

NH

H3N

3.18

47% HBr

3.21

30% H2O2

3.20 3.3

X XX

X X

X=H 3.3aX=Me 3.3bX=Br 3.3c

X=H 3.16aX=Me 3.16bX=Br 3.16c

Chapter 3

58

For the oxidation reaction hydrogen peroxide was chosen, since this gives a clean reaction and no salts are formed, as is the case with for instance KMnO4. However, the work-up procedure should be safe and immediate evaporation of the solvent with still peroxides left in the reaction mixture is obviously too dangerous. We decided to react the remaining peroxide after the reaction with dimethylsulfide, which gives dimethylsulfoxide and this can be removed via evaporation. Peroxide test strips were used to see if all peroxides had reacted with the DMS, also during evaporation. This procedure worked well and we obtained racemic 3.3a in 77% yield. The sulphonic acid 3.3 was isolated as its sodium salt 3.13, since the free sulphonic acid is slightly unstable19c and the formation of the sodium salt provides an extra means of purification.

An induction time was observed in the oxidation reaction with hydrogen peroxide and this can be dangerous since the reaction is exothermic. Apparently the oxidation follows a three-step route, as was found for benzylthiol 3.22 (Scheme 3.7).25

Scheme 3.7 Oxidation of benzylthiol 3.22 with hydrogen peroxide according to Smythe25

First the thiol 3.22 is oxidized to the disulfide 3.23, which is known to be exothermic25 and subsequently this disulphide 3.23 is oxidized to benzyldisulphoxide 3.24, which is transformed into the sulphonic acid 3.25. It could well be that the oxidation of 1-phenylethanethiol 3.20 also proceeds via this stepwise procedure and that one of the three oxidation steps is substantially slower than the other two, causing the induction time.

This route also worked for the synthesis of substituted 1-phenylethane sulphonic acids 3.3b and 3.3c and we prepared these p-substituted derivatives on multi-gram scale, starting from the corresponding p-substituted acetophenones 3.16b and c. Details are given in Table 3.1. To the best of our knowledge, compounds 3.3b and 3.3c have not been described before.

SHS

SS

SO

O

O

O

SO3H

H2O2 H2O2

H2O2

3.22 3.23 3.24

3.25


59

Table 3.1 Results of the synthesis of 3.3a-e

Entry Compound Yield 3.18 (%) Yield 3.20a (%) Yield 3.3 (%) Overall (%)

1 a 98 75 77 57

2 b 98 87 -b < 85

3 c -c 64 87 ≤ 56

a Overall yield of the thiol from the corresponding alcohol 3.18 b Not determined, because traces DMSO left

c Available at Syncom

3.7 Resolution of (substituted) 1-phenylethane sulphonic acids 3.3

The resolution of 3.3 was conducted via the sodium salt 3.13 with L-p-hydroxyphenylglycine 3.26, as described by Yoshioka and co-workers. (Scheme 3.8).26

Scheme 3.8 Resolution of 3.13a with L-p-hydroxyphenylglycine 3.26

The absolute configuration of the less-soluble and more-soluble salt was determined by X-ray analysis26c and is shown in Scheme 3.8 for the unsubstituted sulphonate 3.13a.

The resolution of the p-substituted 1-phenylethane sulphonic acids 3.13a-c was performed with L-3.26 on multi-gram scale and the results are shown in Table 3.2. Unfortunately no HPLC-method could be devised to determine the ee in the resolution of 3.13c.

As far as we know, only 2,3,4-trichloro-1-phenylethanesulphonic acid was described before as a substituted phenylethane sulphonic acid and used in a resolution.27 Unfortunately, the synthesis and resolution are not well documented. 3,4-Dimethoxy-1-phenylethane sulphonic acid was also mentioned, but only in racemic form.28

SO3Na OH

H2NOH

O

L-3.26

10% HCl

SO3

3.13aOH

H3NOH

O

(L)-3.26/(S)-3.3less-soluble salt

SO3

OH

H3NOH

O

(L)-3.26/(R)-3.3more-soluble salt

Chapter 3

60

Table 3.2 Resolution of sulphonates 3.13a-3.13e with L-3.26

Entry Racemate Yield (%) (after rec)

Ee (%) (after rec)

S-factor

1 3.13a 36(27) 87(98) 0.63 2 3.13b 17(6.5) ?a (85) 3 3.13c 15 ?b

a Ee could not be determined because no base line separation was observed b No HPLC-method could be devised to determine the ee

3.8 Large scale synthesis

The newly developed synthesis was subsequently tested on large scale, i.e. starting from 1 L of acetophenone 3.16a (8.6 mol). In the first step, the reduction to the alcohol 3.18a, the addition of 3.16a to the solution of NaBH4 in ethanol takes around 6 hrs, which is possible in one day. On an industrial scale this would not be a problem, since the addition can be controlled properly. The product is isolated via an extraction procedure, but on an industrial scale it should be possible to first evaporate the solvent and subsequently distill the product from the remaining salts.

The next step is the formation of the thiourea salt 3.21. Thiourea is rather toxic, but the reaction is very clean. In order to form the thiol 3.20, a large amount of sodium hydroxide needs to be added and probably more NaCl is produced in this reaction than product. However, since the starting materials are so cheap29 and the yields are high, it is most likely not a problem.

The oxidation reaction is a little bit tricky, since it can be that the oxidation does not start immediately on addition of peroxide; there is an induction time and the chemist should be well aware of that. The reaction is somewhat exothermic, but if already a lot of peroxide is present, it can become very warm. It might be possible to perform the addition at elevated temperatures, but this needs to be explored, for each sulphonic acid separately.

The yields of the large scale reactions are shown in Table 3.3.

Table 3.3 Large-scale synthesis of 3.3a-c

Entry Compound Yield 3.18 (%) Yield 3.20a (%) Yield 3.3 (%) Overall (%)

1 a 94 77 84 61

2 b 96 83 43 34

3 c 96 85 87 71

a Overall yield of the thiol from the corresponding alcohol 3.18


61

The resolutions were also carried out on a larger scale and the results turned out to be comparable to the multi-gram experiments shown in Table 3.2, but need further optimization.

3.9 Conclusions

Two new classes of possible resolving agents have been successfully synthesized from camphor sulphonic acid 3.1. The resolutions with the benzylidene camphor sulphonates 3.8 were not successful, since the resolving agent itself was prone to precipitation. Apparently these compounds as salts with amines do not fit in a crystal structure. Resolutions with the benzyl camphor sulphonates 3.11 did not lead to the desired results, since no precipitation occurred at all. Neither set of compounds seems to be suitable as resolving agent.

A new synthetic route for the preparation of 1-phenylethane sulphonic acids 3.3 was developed and applied on multi-gram as well as on large scale. The resolution was performed with L-3.26, but on large scale this needs further optimization.

3.10 Experimental section

General information Starting materials were commercially available and were used without further purification. Melting points were determined on a Mettler Toledo DSC-822e apparatus with a heating rate of 10 °C/min in standard aluminum crucibles. 1H-NMR spectra were recorded on a Varian Gemini-200 spectrometer (at 200 MHz) at ambient temperature. The splitting patterns are designated as follows: s (singlet); d (doublet); dd (double doublet); t (triplet); q (quartet); m (multiplet) and br (broad). 13C-NMR spectra were recorded on a varian Gemini-200 (at 50.3 MHz). Chemical shifts are denoted in δ (ppm) referenced to the residual protic solvent peaks. Coupling constants J, are denoted in Hz. High resolution mass spectra were recorded on a AEI-MS-902 mass spectrometer by A. Kievit. In the case of 1 mmol resolutions, the salts were removed by filtration on a VacMaster, which is shown in Figure 3.5. Twenty tubes can be filtered at the same time and the mother liquor is collected in test tubes, which are placed in a rack inside the VacMaster. GC measurements were performed on a Agilent 6890 using a flame ionization detector. To ensure accurate ee determination, racemic mixtures were always measured first. Optical rotations were recorded on a Perkin Elmer 241 polarimeter.

Chapter 3

62

Figure 3.5 VacMaster

General procedure for the synthesis of benzylidene camphorsulphonates 3.8: A mixture of camphor sulphonic acid 3.1 (0.08 mol) and NaOMe (0.8 mol, 10 eqv.) was refluxed in toluene (400 mL) for 1 hr. After cooling somewhat, benzaldehyde 3.7 was added (0.08 mol) and the reaction mixture was heated to reflux. After 3 hours at reflux, the mixture was allowed to cool to room temperature overnight. Water (100 mL) was added and after 30 minutes stirring the formed precipitation was removed by filtration. The crude product was recrystallized from water. Sodium benzylidene camphorsulphonate (3.8a): Yield 35% after recrystallization from water. 1H-NMR (DMSO-d6): δ 0.72 (s, 3H), 1.12 (s, 3H), 1.43 (m, 2H), 2.17 (m, 1H), 2.51 (m, 2H), 2.80 (m, 1H), 3.00 (m, 2H), 3.35 (s, 3H), 7.00 (s, 1H), 7.39 (m, 3H), 7.55 (d, 2H); 13C-NMR (DMSO-d6): δ 21.5 (q), 22.7 (q), 27.6 (t), 33.0 (s), 49.2 (t), 50.8 (d), 52.5 (s), 60.0 (t), 129.2 (d), 130.8 (d), 131.4 (d), 131.5 (d), 132.2 (d), 137.5 (s), 144.2 (s), 208.2 (s); mp 173.3-176.9°C. Sodium 4-methylbenzylidene camphorsulphonate (3.8b): Yield 73% after recrystallization from water. 1H-NMR (DMSO-d6): δ 0.67 (s, 3H), 1.08 (s, 3H), 1.36 (m, 2H), 2.18 (m, 2H), 2.30 (s, 3H), 2.97 (m, 1H), 3.11 (m, 2H), 7.03 (s, 1H), 7.21 (d, 2H), 7.40 (d, 2H); 13C-NMR (DMSO-d6): δ 19.6 (q), 20.9 (q), 21.6 (q), 25.8 (t), 26.1 (t), 47.5 (s), 47.8 (t), 49.1 (s), 58.2 (d), 127.8 (s), 132.8 (d), 139.5 (d), 141.3 (s), 206.5 (s); mp 171.2-173.3°C.

Sodium 4-methoxybenzylidene camphorsulphonate (3.8c): Yield 12% after recrystallization from water. 1H-NMR (DMSO-d6): δ 0.16 (s, 3H), 0.52 (s, 3H), 0.99 (m, 1H), 1.14 (m, 1H), 1.68 (m, 1H), 2.02 (m, 1H), 2.47 (d, 1H), 2.88 (d, 1H), 3.28 (s, 3H), 6.38 (d, 2H), 6.60 (s, 1H), 6.88 (d, 2H); 13C-NMR (DMSO-d6): δ 19.5 (q), 20.5 (q), 25.4 (t), 47.1 (t), 48.7 (q), 55.5 (d), 57.8 (s), 114.7 (d), 126.8 (d), 131.7 (d), 139.7 (s), 160.2 (s), 206.0 (s); mp 176.9-180.9°C.


63

General procedure for the hydrogenation of benzylidene camphor sulphonates 3.8: The benzylidene camphor sulphonate 3.8 (5 mmol) was suspended in 90% EtOH (50mL). Pd/C was added (ca. 10 mol%) and the mixture was hydrogenated at 1 bar H2-pressure overnight. The catalyst was removed by filtration over Celite and the filtrate concentrated in vacuo to yield a white solid. The solid was dissolved in water (50mL) with 1 equivalent of NaOH and refluxed overnight. Upon cooling to room temperature a white solid precipitated, which was removed by filtration. Sodium benzyl camphorsulphonate (3.11a): Quantitative yield; final ratio of diastereomers 1:7. 1H-NMR (DMSO-d6): δ 0.77 (s, 3H), 1.11 (s, 3H), 1.19 (m,1H), 1.71 (m, 2H), 2.43 (m, 2H), 2.54 (m, 2H), 2.88 (m, 2H), 3.61 (m, 1H), 7.12-7.21 (m, 5H); 13C-NMR (DMSO-d6): δ 20.2 (q), 21.4 (q), 26.5 (t), 32.4 (t), 45.9 (t), 46.9 (t), 47.5 (s), 61.0 (d), 125.7 (d), 128.3 (d), 131.1 (d), 131.5 (d), 132.3 (d), 139.4 (s), 207.0 (s). Sodium 4-methylbenzyl camphorsulphonate (3.11b): Yield after complete epimerization 30%, 1H-NMR (DMSO-d6): δ 0.76 (s, 3H), 1.04 (s, 3H), 1.19 (m, 1H), 1.62 (m, 3H), 2.22 (s, 3H), 2.34 (m, 3H), 2.55-2.94 (m, 3H), 7.07 (m, 4H); 13C-NMR (DMSO-d6): δ 20.1 (q), 21.1 (q), 26.2 (q), 32.6 (t), 45.9 (t), 46.8 (t), 47.8 (t), 51.3 (d), 60.1 (s), 129.0 (s), 129.7 (s), 135.5 (d), 137.6 (d), 218.3 (s). Sodium 4-methoxybenzyl camphorsulphonate (3.11c): Yield 24%, final ratio diastereomers 1:9. 1H-NMR (DMSO-d6): δ 0.78 (s, 3H), 1.04 (s, 3H), 1.19 (m, 1H), 1.63 (m, 2H), 2.35 (m, 2H), 2.53 (m, 2H), 2.89 (m, 2H), 3.30 (m, 1H), 3.68 (s, 3H), 6.79 (d, 2H), 7.12 (d, 2H); 13C-NMR (DMSO-d6): δ 20.3 (q), 21.0 (q), 26.2 (d), 32.1 (t), 45.9 (t), 46.8 (q), 47.8 (t), 51.4 (t), 55.7 (d), 60.1 (s), 114.5 (d), 130.1 (d), 132.5 (s), 158.2 (s), 218.4 (s). General procedure for the attempted resolutions: 1 mmol of sulphonate was weighed in a test tube. The appropriate solvent was added and subsequently the racemate. The mixture was heated until a clear solution was obtained; addition of extra solvent was sometimes necessary. The mixture was allowed to crystallize at room temperature. If a precipitation formed, this was removed by filtration under suction on the VacMaster. The precipitate was analyzed by 1H-NMR. General procedure for the reduction of acetophenones 3.16 to alcohols 3.18: To a suspension of sodium borohydride (5.8 g; 0.16 mol) in EtOH (120 mL) was added at 0ºC the acetophenone 3.16 (0.32 mol) (in case of the p-Br acetophenone 3.16c this was a solution in EtOH) dropwise, while maintaining the temperature below 10 ºC. After addition is complete, the reaction mixture was stirred overnight at room temperature. After addition of water (100 mL), the mixture was stirred at room temperature for 15 minutes. The reaction mixture was extracted with ether (3 100mL). The combined ether layers were washed with brine, dried over Na2SO4 and concentrated to a colourless liquid.

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1-Phenyl-ethanol (3.18a): Yield 98%; 1H-NMR (CDCl3): δ 1.54 (d, 3H), 2.98 (bs, 1H), 4.91 (q, 1H), 7.32-7.45 (m, 5H); 13C-NMR: δ 25.1 (q), 70.2 (d), 125.5 (d), 127.4 (d), 128.5 (d), 145.9 (s). 1-p-Tolyl-ethanol (3.18b): Yield 98%; 1H-NMR: δ 1.14 (d, 3H), 1.60 (bs, 1H), 2.02 (s, 3H), 4.54 (q, 1H), 6.83 (d, 2H), 6.93 (d, 2H); 13C-NMR: δ 20.8 (q), 24.8 (q), 70.0 (d), 125.2 (d), 129.0 (d), 137.0 (s), 142.8 (s). 1-(4-Bromo-phenyl)-ethanol (3.18c): Available from Syncom; 1H-NMR: δ 1.40 (d, 3H), 4.80 (q, 1H), 7.20 (d, 2H), 7.42 (d, 2H); 13C-NMR: δ 25.0 (q), 69.6 (d), 121.0 (s), 127.0 (d), 131.4 (d), 144.7 (s). General procedure for the formation of thiourea salts (3.21): A mixture of the alcohol 3.18 (0.10 mol), thiourea (0.10 mol), 48% HBr (40 mL) and EtOH (50 mL) was refluxed overnight. After cooling to RT, the reaction mixture was concentrated in vacuo, yielding a white solid or a syrup, depending on the substituent. This crude salt was used without further purification. General procedure for the hydrolysis of the thiourea salts (3.21) to the thiols (3.20): The thiourea salt 3.21 (0.10 mol) was dissolved or suspended in water (50 mL) and heated to 50ºC. To this mixture was added dropwise 33% NaOH solution until no more cloudiness developed upon addition and the pH had risen to 10. The reaction mixture was stirred overnight at 50ºC. After cooling to RT, 30% HCl was added until pH = 6. The reaction mixture was extracted with ether (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to a liquid. NOTE: the thiols 3.20 have a distinct odor! 1-Phenyl-ethanethiol (3.20a): Yield 75%; 1H-NMR: δ 1.67 (d, 3H), 4.23 (q, 1H), 7.35 (m, 5H); 13C-NMR: δ 25.9 (q), 38.5 (d), 126.2 (d), 127.0 (d), 128.5 (d), 144.8 (s). 1-p-Tolyl-ethanethiol (3.20b): Yield 87%; 1H-NMR: δ 1.64 (d, 3H), 2.32 (s, 4H), 4.19 (q, 1H), 7.11 (d, 2H), 7.24 (d, 2H); 13C-NMR: δ 20.8 (q), 25.9 (q), 38.2 (d), 126.1 (d), 129.2 (d), 136.7 (s), 142.8 (s). 1-(4-Bromo-phenyl)-ethanethiol (3.20c): Yield 64%; 1H-NMR: δ 1.80 (d, 3H), 4.12 (q, 1H), 7.19 (d, 2H), 7.38 (d, 2H); 13C-NMR: δ 25.7 (q), 37.9 (d), 120.6 (s), 128.0 (d), 131.6 (d), 144.8 (s). General procedure for the oxidation of thiols 3.20 to 3.3: The thiol 3.20 (36 mmol) was dissolved in acetic acid (120 mL). Hydrogen peroxide (110 mL 30%; 2eq.) was added dropwise, at such a rate that the temperature remains below 32ºC. Beware of the induction


65

time of the reaction; the temperature rise does not follow the addition immediately. After addition is complete and the thiol has reacted (according to TLC), dimethylsulfide was added at 0ºC until no more peroxides were present, as shown by a peroxide test. The reaction mixture was concentrated in vacuo (during evaporation the peroxide test was also applied), yielding an oil (3.3). This residue was suspended in water (ca. 80 mL) and 33% NaOH was added until pH=7. The waterlayer was washed with ether (3 × 75 mL) and concentrated in vacuo to yield the sodium sulphonate 3.13, which was dried in vacuo at 60ºC. 1-Phenylethane-sulphonic acid (3.3a): Yield 77%; 1H-NMR (DMSO): δ 1.51 (d, 3H), 3.83 (q, 1H), 7.27 (m, 5H), 11.5 (bs, 1H); 13C-NMR (DMSO): δ 17.5 (q), 59.9 (d), 126.6 (d, 127.6 (d), 128.9 (d), 139.9 (s). 1-p-Tolylethane sulphonic acid (3.3b): Yield not determined, since still traces of DMSO left; 1H-NMR (D2O): δ 1.74 (d, 3H), 4.24 (q, 1H), 7.34 (d, 2H), 7.44 (d, 2H). 1-(4-Bromo-phenyl)-ethane sulphonic acid (3.3c): Yield 87%; 1H-NMR (D2O): δ 1.75, 4.00 (q, 1H), 7.23 (d, 2H), 7.39 (d, 2H). (d, 3H); 13C-NMR (D2O): δ 15.5 (q), 60.0 (d), 121.2 (s), 130.4 (d), 131.2 (d), 136.3 (s). Resolution of 3.13a:26a Sulphonate 3.13a (50 g; 0.24 mol) was dissolved in 10% HCl (150 mL). L-3.26 (40.1 g; 0.24 mol) was added together with 450 mL 10% HCl and the mixture was heated until a clear solution was obtained. The mixture was allowed to crystallize at room temperature overnight. The resulting crystals were removed by filtration under suction, washed with ice water, furnishing 30.3 g (36%) of a white solid. [α]D=–83.9˚ (c=1, MeOH). HPLC (Ultron ES OVM, 20 mM KH2PO4:CH3CN=95:5)): 87% ee (HPLC). The salt was recrystallized from 10% HCl and little MeOH to afford 22.8 g (27%) of a white solid. HPLC: 98% ee. The salt was suspended in water (25 mL) and heated to 60˚C until a clear solution was obtained. Ammonia (6N) was added until pH=7. The mixture was stirred at 0˚C for 2 hrs. The resulting solid was removed by filtration and the filtrate was passed over Amberlite IR-120. The column was eluted with water. The eluate was concentrated in vacuo and stripped with toluene to obtain 14.5 g of the free sulphonic acid. HPLC: 98% ee. Resolution of 3.13b: Sulphonate 3.13b (140.7 g; 0.63 mol) was suspended in 10% HCl (200 mL). L-3.26 (105.2 g; 0.63 mol) was added and heated until a clear solution was obtained. The mixture was allowed to crystallize at room temperature overnight. The resulting crystals were removed by filtration under suction, washed with ice water, furnishing 39.3 g (17%) of a white solid. HPLC showed unfortunately no base line separation. The salt was recrystallized from 10% HCl and MeOH to afford 15.1 g (6.5%) with 85% ee. [α]D=–74.2˚ (c=0.5, MeOH). Due to low yield this salt was suspended in 20 mL water and heated to 60˚C. Ammonia (6N) was added until pH=7. The mixture was stirred at 0˚C for 2 hrs. The resulting solid was removed by filtration and the filtrate was passed over Amberlite IR-120. The

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column was eluted with water. The eluate was concentrated in vacuo and stripped with toluene to obtain 14.5 g free sulphonic acid, which still contained some water. Resolution of 3.13c: Sulphonate 3.13c (2.0 g; 7 mmol) was suspended in 10% HCl (40 mL). L-3.26 (1.16 g; 7 mmol) was added and heated until a clear solution was obtained. The mixture was allowed to crystallize at room temperature overnight. The resulting crystals were removed by filtration under suction, washed with ice water, furnishing 0.45 g (15%) of a white solid. [α]D=–64.6˚ (c=0.5, MeOH). Unfortunately no HPLC-method could be devised to determine the ee. Due to low yield this salt was suspended in 5 mL water and heated to 60˚C. Ammonia (6N) was added until pH=7. The mixture was stirred at 0˚C for 2 hrs. The resulting solid was removed by filtration and the filtrate was passed over Amberlite IR-120. The column was eluted with water. The eluate was concentrated in vacuo and stripped with toluene to obtain 50 mg free sulphonic acid, which still contained some water.

3.11 References

1 (a) Sheldon, R.A. Chirotechnology, Marcel Dekker, New York, 1993; (b) Collins, A.N.; Sheldrake, G.N.; Crosby, J. Chirality in Industry, John Wiley and Sons, Chichester, 1992.

2 Newman, P. Optical Resolutions Procedures for Chemical Compounds, Optical Resolution Information Centre, New York, 1971.

3 The use of 3.3 has been described in many patents, see e.g.: (a) Chibata, I.; Yamada, S.; Hongo, C.; Yoshioka, R. Eur. Pat. Appl. 1984, 0 119 804; (b) Senhata, I.; Yamada, S.; Hongo, C.; Yoshioka, R. 1983, JP58052254A2; (c) Chibata, I.; Yamada, S.; Hongo, C.; Yoshioka, R. 1985, US4,519,955; (d) Tosa, T.; Osamuu, O.; Yoshioka, R. 1989, JP01029345A2; (e) Senhata, I.; Yamada, S.; Hongo, C.; Yoshioka, R. 1983, JP58052253A2; (f) Chibata, I.; Yamada, S.; Hongo, C.; Yoshioka, R. 1983, US4,415,504; (g) Senhata, I.; Yamada, S.; Hongo, C.; Yoshioka, R. 1984, JP59170059A2.

4 (a) Kozma, D. CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation, Boca Raton, 2002; (b) Wilen, S.H. Tables of Resolving Agents and Optical Resolutions, Eliel, E.L. (eds), University of Notre Dame Press, London, 1972.

5 See e.g. (a) Yan, T.-H.; Chu, V.-V.; Lin, T.-C.; Wu, C.-H.; Liu, L.-H. Tetrahedron Lett. 1991, 32, 4959; (b) Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett. 1989, 30, 5603; (c) Ahn, K.H.; Lim, A.; Lee, S. Tetrahedron: Asymm. 1993, 4, 2435; (d) Chandrasekhar, S.; Kausar, A. Tetrahedron: Asymm. 2000, 11, 2249.

6 Yoshioka, R.; Hiramitsu, H.; Okamura, K.; Tsujioka, I.; Yamada, S. J. Chem. Soc. Perkin Trans 2, 2000, 2121 and references therein.

7 (a) Boesten, W.H.J. US Patent 4,111,980; 1978; (b) Bruggink, A.; Roos, E.C.; De Vroom, E.; Org. Process. Res. Dev. 1998, 2, 128-133; (c) ref. 1b, p. 187-208.

8 Ref 1a, p.190-191.


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9 p-Hydroxyphenylglycine can be resolved with 3.1 in mixtures with phenylglycine; see Kaptein, B.; Elsenberg, H.; Grimbergen, R.F.P.; Broxterman, Q.B.; Hulshof, L.A.; Pouwer, K.L.; Vries, T.R. Tetrahedron: Asymm. 2000, 11, 1343.

10 Yamada, S.; Hongo, C.; Yoshioka, R.; Chibata, I. Agric. Biol. Chem. 1979, 43, 395. 11 (a) Bouillon, C.; Vayssie, C.; Richard, F. US Patent 4,304,730; 1981; (b) Bouillon, C.; Vayssie,

C.; Richard, F. US Patent 4,330,488; 1982; (c) Bouillon, C.; Vayssie, C.; Richard, F. US Patent 4,323,549; 1982 and patents cited herein.

12 Evans, E.B.; Mabbott, E.E.; Turner, E.E. J. Chem. Soc. 1927, 1159. 13 (a) Anderson, A.R.; Short, W.F. J. Chem. Soc. 1933, 485; (b) Agami, C.; Prince, B.; Puchot, C.

Synth. Commun. 1990, 20, 3289; (c) Ashworth, F.; Burkhardt, G.N. J. Chem. Soc. 1928, 1791; (d) for a review on sulfonation reactions see: Gilbert, E.E. Synthesis 1969, 1, 3.

14 Faber, W. unpublished results. 15 Kharasch, M.S.; May, E.M.; Mayo, F.R. J. Org. Chem. 1938, 3, 175. 16 Suter, C.M.; Bayard Milne, H. J. Am. Chem. Soc. 1943, 65, 582. 17 Miller, W. Justus Liebigs. Ann. 1877, 189, 338. 18 Corey, E.J.; Cimprich, K.A. Tetrahedron Lett. 1992, 33, 4099. 19 (a) Corey, E.J.; Bakshi, R.K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551; (b) Corey, E.J.;

Shibata, S.; Bakshi, R.K. J. Org. Chem. 1988, 53, 2861; (c) Corey, E.J.; Bakshi, R.K. Tetrahedron Lett. 1990, 31, 611.

20 The corresponding alcohol is available from Acros: (R)-(+)-α,α-diphenyl-2-pyrrolidinemethanol 1 g € 124.52 and (S)-(+)-α,α-diphenyl-2-pyrrolidinemethanol 1 g € 25.53.

21 Levene, P.A.; Mikeska, L.A. J. Biol. Chem. 1927, 75, 587. 22 Firouzabadi, H.; Salehi, P.; Mohammadapour-Baltork, I. Bull. Chem. Soc. Jpn. 1992, 65, 2878. 23 Capozzi, G.; Modena, G. The Chemistry of the Thiol Group, Part 2, Wiley, New York, 1974, p.

785. 24 (a) Douglass, I.B.; Johnson, T.B. J. Am. Chem. Soc. 1938, 60, 1486; (b) Ziegler, C. Sprague, J.M.

J. Org. Chem. 1951, 16, 621. 25 Smythe, J.M. J. Chem. Soc. 1912, 2076. 26 (a) Yoshioka, R.; Tohyama, M.; Ohtsuki, O.; Yamada, S.; Chibata, I. Bull. Chem. Soc. Jpn. 1987,

60, 649; (b) Yoshioka, R.; Ohtsuki, O.; Senuma, M.; Tosa, T. Chem. Pharm. Bull. 1989, 37, 883; (c) Yoshioka, R.; Ohtsuki, O.; Da-Te, T.; Okamura, K.; Senuma, M. Bull. Chem. Soc. Jpn. 1994, 67, 3012; (d) Yoshioka, R.; Okamura, K.; Yamada, S.; Aoe, K.; Da-Te, T. Bull. Chem. Soc. Jpn. 1998, 71, 1109.

27 Kawanishi, H.; Morimoto, H.; Nakano, T.; Watanabe, T.; Oda, K. Tsujihara, K. Heterocycles 1998, 49, 181.

28 (a) Psotta, K.; Forbes, C.P. Tetrahedron 1982, 38, 3585; (b) Glasser, W.G.; Gratzl, J.S.; Collins, J.J.; Forss, K.; McCarthy, J.L Macromolecules 1973, 6, 114.

29 The price for 1 kg of thiourea at Acros is € 21.15.

resolutions with families of resolving agentsit turns out that strongly acidic resolving agents,...

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