Design and evaluation of inclusion resolutions, based on readily available host compounds

FULL PAPER

Design and Evaluation of Inclusion Resolutions, Based on Readily Available

Host Compounds

Simona Müller,^[a]Marcel Cyrus Afraz,^[a]René de Gelder,^[b]Gerry J. A. Ariaans,^[a]

Bernard Kaptein,^[c]Quirinus B. Broxterman,^[c]and Alle Bruggink*^[a,c]

Keywords: Inclusion / Chiral resolution / Host-guest systems / Enantioselectivity

Resolution of enantiomers through selective crystallisation of

diastereomeric inclusion compounds can extend the scope of

traditional racemate resolution beyond salt forming com-

pounds. To assess the practical value of this approach the

literature was carefully screened and promising results were

checked. Also an extensive range of new inclusion hosts suit-

able for resolution processes, derived from simple hydroxy-

and amino acids were prepared and tested. Several tech-

niques, including the Dutch Resolution approach utilizing

mixtures of resolving agents, were applied. Over 70 potential

resolving agents were tested in combinations with 34 race-

mates (over 100 racemates if literature results are included).

Reproducibility of literature results was found to be problem-

atic. Also the number of successful new resolutions found

was very limited: only two efficient resolutions out of 1200

combinations of racemate and resolving agent tested in over

10.000 experiments! Crystal studies of representative combi-

nations of resolving agents and inclusion compounds re-

vealed some of the causes for the low rate of success in in-

clusion resolution. Compared to diastereomeric salts, the ab-

sence of strong electrostatic interactions substantially re-

duces the probability of forming crystals including both com-

ponents. Molecular structure features allowing formation of

intricate intramolecular and intermolecular H-bond networks

were found to be responsible for inclusion crystal formation,

and for the quality of the ensuing resolution through selec-

tive diastereomer crystallisation, in the successful cases.

Whereas diastereomeric salt resolution continues to be of sci-

entific and industrial interest, inclusion resolution should be

viewed as of very limited scope; useful in specific instances,

but lacking the wide applicability of classical resolution.

Germany, 2005)

be a new lead towards removal of this limitation. The ready

availability of a variety of host compounds, required for

formation of the enantioselective inclusion complexes, de-

rived from simple and inexpensive enantiopure hydroxy ac-

ids such as tartaric acid and lactic acid, is an additional

advantage.

Introduction

Diastereomers take a prominent place in preparing op-

tically pure compounds through resolution of racemates. In

particular diastereomeric salts have a long history − well

over 100 years − in mediating access to functional enantio-

pure molecules at any scale, ranging from milligrams for

test purposes to multi-thousand tons production units for

established fine chemical intermediates. Covalent dia-

stereomers are far less frequently used, mainly because ad-

ditional chemical operations are required before and after

the resolution step. This disadvantage by far outweighs the

main limitation of using diastereomeric salts, i.e. being re-

stricted to the resolution of acids and bases. Within this

context the development of resolutions through inclusion

complexes by Toda^[1]and other researchers^[2]promised to

From a more fundamental viewpoint, inclusion resolu-

tions through selective crystallisation of diastereomeric

molecular complexes would allow more in depth crystal

studies aimed at a better understanding of chiral discrimi-

nation in crystal nucleation and crystal growth. In such

complexes the stereoselective interactions can be more eas-

ily identified, as they are not overwhelmed by the strong

electrostatic interactions present in diastereomeric salts.

This in turn could lead to a more rational approach in the

design and application of resolving agents. Thus far, our

studies and related research by others have shown an ongo-

ing synergistic development between increased fundamental

understanding and rational design of resolutions through

selective crystallisation on one hand, and additional insight

through practical experience, i.e. trial and error, on the

other side. The successful development of cyclic phosphoric

acids as very useful resolving agents by Wynberg and ten

Hoeve exemplifies the rational design.^[3]Crystal studies by

[a] Department of Organic Chemistry, University of Nijmegen,

Toernooiveld 1, 6525 ED Nijmegen, The Netherlands

[b] Department of Inorganic Chemistry, University of Nijmegen,

Toernooiveld 1, 6525 ED Nijmegen, The Netherlands

[c] DSM Research, Life Sciences-Advanced Synthesis & Catalysis

Department,

P. O. Box 18, 6160 MD Geleen, The Netherlands

E-mail: alle.bruggink@dsm.com

Supporting information for this article is available on the

WWW under http://ww w .eurjoc.com or from the author

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DOI: 10.1002/ejoc.200400613

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Design and Evaluation of Inclusion Resolutions

FULL PAPER

Leusen^[4]and by Vlieg and colleagues^[5]show chiral dis-

crimination to be the result of subtle differences in molecu-

lar interactions in solution, crystal nucleation, crystal

growth and the resulting crystal lattice. Asking for predic-

tions in organic multicomponent (and ionic) crystals is still

beyond current scientific and computational capacity.

Results and Discussion

Selection and Preparation of Host Compounds

The easy access to enantiopure tartaric acid and lactic

acid, together with the already known^[1,2]successful results

The discovery of Dutch Resolution, in which a racemate of their diol derivatives in inclusion resolutions, constituted

is resolved with a family of structurally related resolving a straightforward choice for the start of our studies. The

agents, is an outstanding example of gaining further insight range of diols, as published by Toda and Weber, could be

through practical experience. Most likely the effect is caused easily extended by introducing a number of new substitu-

by certain family members acting as nucleation inhibitor for ents. This served to gain better insights in the importance

crystallisation of one of the diastereomeric salts.^[6,7]Sub- of additional interactions in combination with the direct

sequently, proper practical experience has led to the devel- inclusion process, i.e. additional H-bonding, extra steric

opment of a set of resolving agent mixtures, which allows hindrance or reduced symmetry. To test the requirement of

fast and efficient resolution of a wide range of salt forming the diol moiety for success in inclusion resolutions several

racemates. A similar success in resolution through inclusion other derivatives were prepared. For similar reasons deriva-

complexes would greatly enlarge the scope of traditional as tives of malic acid and pantolactone were included.

well as Dutch Resolution processes. Therefore, a wide range Scheme 1 gives an overview of the host molecules used in

of potential host compounds for complex formation was this study. The Taddols 1c, f, j, k, l are new as well as the

prepared, and tested with a variety of racemates for forma- lactic acid derivatives 2b, e–g, i–n and the potential hosts 3

tion of inclusion compounds and possible resolution prop- and 4.

erties. The scope of inclusion resolution was found to be

As a potentially useful widening of the scope of inclusion

more limited than initially expected based upon the results resolutions also some readily available amino acids were

published so far in literature. Supporting spectral and crys- chosen as starting materials for new host molecules. In or-

tal studies were performed, which led to a better under- der to cover a wide range of molecular diversity amino

standing of the experienced limitations, and which may be alcohols derived from alanine, phenylalanine, phenylglycine

useful for future applications of this method.

and proline were chosen; see Scheme 2. Also a number of

Scheme 1. Potential host compounds derived from enantiopure hydroxy acids.

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Eur. J. Org. Chem. 2005, 1082–1096

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Scheme 2. Potential host compounds derived from amino acids.

N-acylated amino alcohols were included. Several of these number of acids and bases, which can be resolved by other

compounds are new, i.e. 5c, f, g, h, j, k, l and all representa- known methods, have been included; 34 racemates were

tives of 6 and 7 except 6a, 6i and 7a, and none of them tested in our studies. Together with the 100 examples al-

have been used in studies on inclusion resolutions. In total ready published but covering a smaller molecular diversity,

over 70 host compounds were prepared, many of them rep- a fair presentation of the scope and limitations of inclusion

resenting new examples of known types of derivatives. All resolutions should be possible.

compounds could be obtained employing known synthetic

methods. Further details are available as Supporting Infor-

mation.

Resolution Experiments

Several standard methods for the execution of inclusion

[8]

resolution experiments have been described.

The first,

Selection of the Racemic Guest Compounds

and most common is the combination of a host and a guest

The racemates, i.e. the guests in the inclusion compounds compound in a solvent, followed by crystallisation from

to be formed, should represent a broad range of molecular solution. Since the optimal combination ratio is not known,

diversity. All guests described in the literature so far, ap- the use of excess host as well as high excesses of guest is

proximately 100, are relatively small compounds and most possible. The formation of the inclusion crystal in a well-

contain functional groups, suitable for hydrogen bonding defined host-guest ratio does not depend on the host-guest

with the host molecules. These two criteria have also played ratio in solution, but only on the stability of the inclusion

a major role in the selection of the guests used in the pres- crystal. The resolution process is simple to execute and the

ent research. Moreover, the guest molecules have been se- inclusion compound can be separated easily from the solu-

lected with respect to their industrial relevance and resis- tion. Either liquid or solid guest compounds can be em-

tance to resolution by other known methods. Many of them ployed. However, the solvent itself may also be a suitable

constitute precursors for pharmaceuticals or other fine guest and might eventually become a competitor for the

chemicals. Some of the selected racemates can be racemised actual guest compound.

under mild conditions and are therefore possible candidates

The second method uses a solvent in which host, guest

for the application of asymmetric transformation. Table 1 or both are poorly soluble and a slurry is obtained. In this

gives an overview of all used guest compounds, divided into case the inclusion compound can both be formed by dissol-

different categories. For comparative reasons also a small ution-recrystallisation or by direct absorption into the crys-

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Design and Evaluation of Inclusion Resolutions

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Table 1. List of potential guest compounds used in this study.

Compound

Alcohol

Functionalities

Acid

Amine

Aromatic

Nitrile

Ether

Ketone/ester

G1

1-phenylethylamine

2-phenylglycinonitrile

2-amino-1-butanol

1-amino-2-propanol

2-amino-1-propanol

2-amino-3-methyl-1-butanol

3-pyrrolidinol

trans-2-methoxycyclohexanol

trans-2-methylcyclohexanol

cis-2-methylcyclohexanol

1-phenoxy-2-propanol

1-phenylethanol

tetrahydrofurfuryl alcohol

1-tert-butoxy-2-propanol

2-butanol

1,2-propanediol

5-hydroxy-3-methyl-2,5-dihydro-2-fu-

ranone

᭹

G2

᭹

G3

᭹

G4

G5

G6

G7

G8

᭹

G9

G10

G11

G12

G13

G14

G15

G16

G17

᭹

G18

G19

G20

G21

G22

G23

G24

G25

G26

G27

G28

G29

3-nitro-2-pentanol

3-nitro-2-butanol

lactic acid

lactonitrile

mandelonitrile

solketal

1-phenyl-1,2-ethanediol

β-(chloro)isobutyric acid

ibuprofen

2-methoxycyclohexanone

5-methoxy-5H-furan-2-one

3,3a,4,8b-tetrahydro-2H-indeno[1,2b]fu-

ran-2-one

᭹

G30

G31

G32

G33

G34

propylene oxide

᭹

methyl phenyl sulfoxide

3-methylcyclohexanone

3-aminopyrrolidine

trans-3-methylcyclohexanol

᭹

tal lattice of a solid host. An advantage of this approach is equipment makes the vapour sorption method the least

that the solid material can act as a suitable template for favourable one.

nucleation, leading to easier preparation of a first batch of

crystals.

Given the limited number of useful results in our elabo-

rate experiments (see below) all methods were tested. More-

The third method applied does not involve the use of any over, all known tricks and techniques to enhance crystallis-

solvent. In this case either host or guest must be a liquid in ation were applied, including slow evaporation of solvent,

which the other compound is dissolved or suspended. Sim- gradual temperature changes, the use of solvent mixtures

ple grinding in a mortar sometimes works. ^[9]The separation (several host compounds do crystallise only as a solvate;

of the solid inclusion compound from the excess of liquid also several inclusion complexes containing hydrates or sol-

guest can be more difficult. The major disadvantage of this vates are known^[10,11]), ultrasonic treatment after gel forma-

technique is the restriction to the use of liquid hosts or tion, high pressure (up to 15 kbar) and the application of

guests.

Finally, the fourth method used in inclusion experiments

mixtures of hosts (the Dutch Resolution approach).

is the sorption technique. In this method the gaseous guest

compound is allowed to flow over the solid host compound

and can be absorbed into the host’s crystal lattice. Obvi-

Results of Inclusion Experiments

The number of successful resolutions was surprisingly

ously, this technique is restricted to compounds, which are low. Also reproduction of literature results was by no means

stable enough to be transferred into the gaseous phase. a straightforward procedure. With 70 host compounds and

Thus, only small sized molecules with low boiling points 34 guest molecules in hand we performed several thousands

are suitable for this approach. Also the need for special of inclusion attempts using several of the methods summa-

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rised above. Successful inclusion formations are given below new. The remaining 90% of our experiments gave − in equal

together with an impression of the failed attempts. numbers − formation of gels, or crystalline pure host com-

Reproducibility: Experience in resolution through selec- pounds without guest included. See Table 3 for an overview

tive crystallisation teaches prudence in repeating literature of successful inclusion resolutions, and Table 4 for an over-

results. Exact experimental conditions are often difficult to view of inclusions with inclusion of the racemic guest.

record. In particular crystal nucleation can be notorious in

Table 3. Successful inclusion resolution experiments with Taddols.

terms of reproducibility. Table 2 shows the poor reprodu-

cibility of literature procedures for inclusion resolutions in

our hands.

Host Guest Ra- Chirality

ee/

Method

Yield

S

Recovery

method^[a]

tio

guest

Five attempts to repeat resolutions described by Toda

(Entries 1–5), led in only one case to the documented in-

clusion complex (Entry 3). The resolution efficiency ap-

pears to be lower. In the other four batches pure crystals of

the respective Taddols were obtained. Also results described

by Weber using lactic acid derivative 2a were only poorly

reproducible. Resolutions of phenethylamine were unsuc-

cessful in our hands as well as those with methyl cyclohexa-

nol as guest racemate. Resolutions of methyl oxirane and

1b

1d

1i

G20

G1

G8

G5

G20

2:1

1:1

2:1

1:1

2:1

(S)

L

(R,R)

n.d.

(S)

71% / I

95% / A

94% / D

21% / A

66% / I

11%

41%

39%

24%

19%

0.1

0.8

0.1

0.2

MeOH

1j

[a] MeOH: inclusion crystallisation of host with methanol, followed by

standard isolation of guest.

Attempts to increase the score of positive results through

methyl phenyl sulfoxide could be reproduced although with the application of various other experimental set-ups were

varying results. Summarizing, only 3 out of 10 literature rather poor. We first attempted to induce crystallisations in

examples could be reproduced and, moreover, with varying solution at pressures up to 15 kbar. With this approach only

results.

the combination of 1d with trans-2-methoxycyclohexanol

Taddols as Hosts: Almost 200 successful inclusions have (G8) produced inclusion crystals, furnishing the seeds for

been described by Toda and co-workers, ^[18]involving close the positive result listed above. Repeating the successful res-

to 100 racemates, but using only 5 differently substituted olution of phenylethylamine at pressures ranging from 3–15

Taddols (1a, b, d and 1i, m with R¹, R²= (CH₂)₄resp. kbar showed a small but consistent drop in ee.

(CH₂)₅and Ar = phenyl) as resolving agents. In general the

Another 80 experiments using no solvent (using liquid

quality of these resolutions is excellent: Over 80% ee in guests in excess) did not give a single additional positive

50% of all cases. Combined with yields of 80% (maximum result, although the successful resolution of phenylethylam-

yield of one enantiomer defined as 100%) or above the ine could be reproduced albeit with an ee of 72% compared

score drops to below 10%. All the latter results were ob- to 95% under solution conditions. Also vapour sorption

tained with Taddols bearing a phenyl group as aryl substit- techniques and grinding experiments gave no additional re-

uent; 1a being the most successful resolving agent. Em- sults, only showing that the good resolution of phenylethyl-

ploying the solution method we performed 360 resolution amine with 1d could be repeated, although with poorer effi-

attempts representing the 12 host Taddols 1a–l and 34 of ciencies. We took our next resort to the Dutch Resolution

our guest racemates, G1–34. Inclusion crystals were ob- approach using 10 different mixtures of the Taddols 1a–l,

tained in 10% of all cases. Only 5 examples showed resolu- each mixture consisting of 2 or 3 host molecules. In 300

tion of which a mere two with a quality of 0.8 (defined as experiments, using 30 guest racemates G1–34, 22 crystalline

S = 2 × ee × yield), both using 1d as resolving agent. One inclusion complexes were obtained. In 30% of our experi-

of the involved racemates, phenylethylamine, G1, has been ments gels were formed, whereas over 60% resulted in crys-

resolved before through selective inclusion using 1a as re- tallisation of one or more host compounds containing no

solving host with a resolution quality of 0.58.^[12]The suc- guest molecules. Compared to the 1:1 solution experiments

cessful resolution of trans-2-methoxycyclohexanol (G8), is the success rate is lower. Moreover, in all inclusion cases

Table 2.Reproducing literature results in inclusion resolutions.

Literature result

This work

Host Guest

Ref.

Host-guest ratio

ee / Yield

Method

Host-guest ratio

ee / yield

Method

[12]

[10]

1a

1i

2a

G1

G13

G5

G28

G30

G1

2:1

n.d.^[a]

n.d.

1:1

2:1

1:1

91/62%

21/n.d.

69 (+)/n.d. and 100 (+)/n.d.

18(+)/91%

52(+)/n.d.

8 (R) and 2.7 (R)/75%

35.3 (S)/64%

53 (S)/50%

9.3 (R) and 25(R)/90%

32.8 (S)/72%

cryst.

cryst. and fract. dist.

cryst.

cryst. and sorption

cryst.

cryst. and sorption

cryst.

–

1:1

–

2:1

1:1

–

cryst.

[13]

21 (n.d.)/24%

[14]

–

[15]

[11,16]

[10,17]

[17]

G9

G10

G30

G31

–

[17]

10 (R)/25%

87 (S)/30%

[17]

[a] n.d.: not determined.

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Design and Evaluation of Inclusion Resolutions

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Table 4. Successful inclusion experiments without resolution using as above and propylene oxide G30 with 2a as well. In both

Taddols.

cases no resolution was observed. This solvent free ap-

proach gave mainly no crystallisations at all (50%) next to

gels (20%) and host crystals (30%). Exploitation of solvent

mixtures performed even worse, resulting exclusively in gel

formation in 150 experiments. The Dutch Resolution ap-

proach was not any better producing only gels in the ca. 40

experiments employing 2a–d and 12 selected guests: G1, 7–

10, 21, 23, 25, 26, 30, 32, 33. To recheck the failure of this

approach we repeated the resolution of G31, methyl phenyl

sulfoxide, as described by Weber, ^[16,17]under various condi-

tions. Single 1:1 experiments with 2a gave successful resolu-

tions in solution, as well as without additional solvent, with

mediocre and varying efficiency from 0.2–0.4. However, ap-

plication of host mixtures, composed from various combi-

nations of 2a, b, d, and k, completely destroyed these re-

sults: solutions remained clear for several months or stable

gels were obtained resisting all attempts to induce crystal

forming.

Host

Guest

Ratio

Yield

Recovery

method^[b]

1a

1b

1c

1d

1e

G5

G7

G16

G6

G21

G23

G9

G25

G5

G7

G10

G16

G21

G25

G27

G23

1:1

3:2

2:1

1:1

1:2

1:1

2:1

42%

33%

12%

8%

22%

19%

23%

17%

13%

18%

9%

M

B/B

M

18%

22%

23%

19%

B/B

Host

Guest

Ratio

Yield

Recovery

method^[b]

Other Hydroxy Acid Derivatives: Lactic acid-derived hy-

droxy ethers 2l–n and pantolactone derivatives 3a, b as well

as malic acid derivative 4 were tested in a limited experi-

mental set-up. Out of 20 racemates only inclusion crystals

with lactonitrile, G21, were obtained, but unfortunately no

resolution. Gelation was once more the most prominent

phenomenon in all experimental variations, in particular

with 2l and 2n as host molecules.

Amino Acid Derivatives:The amide derivatives 6a–x and

7b–d were tested in a first series of experiments. Given their

capability for intra- and intermolecular H-bond formation

we hoped for inclusion results comparable to the successful

Taddols. Nothing was farther from the truth, however. The

very low solubility of these hosts limited our experimental

space, as inclusion will only occur if the complex has an

even lower solubility. Only DMSO, or in some cases chloro-

form, could be used, next to a solvent free version. Experi-

ments with 24 of our guest racemates did not result in a

single inclusion crystal. The benzhydryl-substituted hosts

1g

1i

G5

G7

1:1

1:2

1:1

1:2

2:3

1:1

1:2

1:1

9%

B/B

M

B/B

31%

22%

24%

5%

11%

19%

22%

21%

34%

25%

27%

33%

24%

27%

37%

G16

G3

1i

G4

1i

G6

1i

G7

1i

G16

G18

G4

1i

1j

G8

1j

G9

1j

G18^[a]

G5

1k

G6

G16

G20

[a] Resolution described in literature. [b] M: inclusion crystallis-

ation of host with methanol, followed by standard isolation of

guest. B/B: isolation of guest molecule by bulb-to-bulb distillation.

only a single resolving host was present, contrary to Dutch all gave gel formation, and the proline derivatives gave clear

Resolutions employing diastereomeric salts. Furthermore, solutions, even after several months. The big majority of all

the quality of these resolutions lies below those of the 1:1 other amide hosts precipitated from the solution as pure

experiments, ranging from 0.2–0.6. The Dutch Resolution compounds, taking several weeks or months to the onset of

approach did, however, result in 4 new crystalline inclusion crystallisation. NMR analysis of the precipitated material

complexes not accessible through 1:1 batches: 1d·G19; proved the absence of any inclusion, neither guest racemate,

1g·G3; 1j·G21 and 1j·G23. Disappointingly though, none of nor solvent or water. Finally, experiments combining the

these complexes showed any optical activity, nor were these amino-alcohols 5a–k with the non-acidic representatives of

racemates resolvable in the 1:1 approach in which they our guest collection resulted only in gels. These experiments

formed inclusion crystals with some of the other host mole- were limited to the Dutch Resolution approach.

cules (see Table 2).

NMR Shift Experiments: Given the limited success in our

Lactic Acid Derivatives As Hosts: A first series of solu- resolution experiments we looked for a quick test indicating

tion experiments using 2a–e as host and a selection of 11 chances for formation of inclusion complexes and resolu-

guests (G1, 7–10, 21, 23, 25–27 and 30) gave only one exam- tion. As taddols have been used as chiral shift reagents for

ple of crystalline inclusion: β-(Chloro)isobutyric acid (G25) ee determination by NMR spectroscopy,^[19]we considered

with 2a but showing no ee. In most cases the host com- this as a useful Entry. A strong interaction in solution, as

pound crystallised (60%) or gels were formed (30%). A indicated by an NMR shift, could indicate a higher prob-

wider series using 7 hosts, 2a–f,k, and 22 of our guest race- ability for the forming of an inclusion complex. For exam-

mates (G1, 3, 4, 6, 7–11, 13–16, 18–21, 23, 25, 27, 30 and ple phenethylamine, which was successfully resolved with

32) in the solvent free fashion resulted in two hits: 2a·G25 Taddol 1a, shows some clear shifting and splitting of NMR

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A. Bruggink et al.

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signals in solutions of the racemate in the presence of this of the observed results. However, studying crystal properties

Taddol.^[19a]

to predict resolutions is a highly risky approach as recently

To test this hypothesis shift experiments were performed mentioned by Dunitz. ^[20]

with racemic lactonitrile and 4 different Taddols. Taddols

1b and 1d were chosen because inclusion crystals (no reso-

lution) were already obtained with lactonitrile in the crys-

tallisation experiments (see Table 4), and Taddols 1a and 1j

because these produced no inclusion crystals. The NMR

signal of the methine proton of lactonitrile was split in the

presence of Taddols 1a, 1b and 1d. In the presence of Tad-

dol 1j no shift of the proton signal of lactonitrile was ob-

served. Although the initial results were not conclusive the

usefulness of NMR in predicting potential host-guest inter-

actions was further explored by studying 4 of our lactic acid

derived hosts, 2a,b,d, and e, with a selection of 11 of our

racemates. Results are collected in Table 5.

Comparing these results with the actually obtained in-

clusion crystals from hosts 2a–k, as described previously, it

becomes quite clear that useful predictions based on NMR

cannot be made. Similar unsatisfactory results were ob-

tained in shift experiments with hosts 2l–n and 3a, b. Also

the application of host mixtures, to predict Dutch Resolu-

tion effects, produced no useful results.

Taddols as Hosts: A literature survey has shown that the

Taddols tend to show characteristic behaviour in binding

to their included guest molecules, independent of the final

complex structure. Depending on the respective guest com-

pound, the Taddols can form cavities, channels or layers, in

which the guest molecule is embedded. Five of the inclusion

complexes obtained in our studies were found to be suitable

for analysis by X-ray: Taddol 1d with (R,S) as well as race-

mic phenylethylamine (G1) and with trans-2-methoxycy-

clohexanol (G8), and Taddol 1j with lactic acid (G20).

In the 1:1 inclusion complex of Taddol 1d and (R)-phen-

ylethylamine the two hydroxy groups of the Taddol mole-

cule are hydrogen-bonded to each other, leaving one hy-

droxy hydrogen in a free position to form a hydrogen bond

to an acceptor site of the guest molecule. Whereas suitable

crystals of (S)-G1 with 1d could easily be obtained, usable

crystals with (S)-G1 could only be obtained containing 65%

(S) only (ee = 30%). Also crystals containing 50% of both

(S) and (R), i.e. the racemate, could be grown. The crystals

with an equal amount of (S) and (R) clearly showed solid

solution of the amine guest. A comparison of the (S) and

(R) structures shows hardly any differences, which is consis-

tent with the results of X-ray powder diffraction analyses,

which were found to be nearly identical (see Figure 1).

In the 2:1 inclusion inclusion complex of Taddol 1d and

(S,S)-trans-2-methoxycyclohexanol (G8) the two hydroxy

groups of both Taddol molecules are again internal hydro-

gen-bonded to each other, leaving one hydroxy hydrogen in

a free position to form a hydrogen bond to the guest mole-

cule or to the other Taddol molecule. In this inclusion com-

plex both Taddols form a dimer, which is then hydrogen-

bonded to the guest. The X-ray crystal structure of this in-

clusion compound is depicted below in Figure 2.

Crystal Studies

We have found that in most cases of successful inclusion

complex formation these can be rationalised in hindsight

using information derived from an X-ray crystal structure

determination. Also crystallisation of the pure host mole-

cule can often be understood by inspecting the crystal struc-

ture. Contrary to resolutions through diastereomeric salts,

where mainly strong ionic forces are directing crystal for-

mation (and in which both ions must be present to maintain

neutrality), participants in inclusion resolutions are in-

volved in more subtle interactions allowing energy minima

In the 2:1 inclusion complex of Taddol 1j and (S)-lactic

in crystals of various compositions: inclusion complexes of acid G20 (Entry 34), the two hydroxy groups of both Tad-

host and guests in various ratio’s and enantiomeric excesses dol molecules are again internal hydrogen-bonded to each

or crystals of hosts with or without inclusion of solvents. other, leaving one hydroxy hydrogen in a free position to

Thus, by studying a large number of crystal structures, both form a hydrogen bond to the guest molecule. In this in-

from the literature and this work, we could rationalize most clusion complex the two Taddols do not form a dimer, but

Table 5. H NMR-shift experiments with lactic acid derived diols.

Guests

Hosts (∆δ = shifting or splitting in ppm)

2a

2b

2d

2e

trans-2-methoxycyclohexanol (G8)

cis-2-methylcyclohexanol (G10)

trans-2-methylcyclohexanol (G9)

3-pyrrolidinol (G7)

β-chloroisobutyric acid (G25)

ibuprofen (G26)

lactonitrile (G21)

0^[a]

0

0.023 (OCH₃)

0

0.020 (OCH)

0.028 (NCH)

0.024 (OCH)

0.023 (OCH)

0.021 (NCH)

0.034 (OCH)

0.038 (NCH)

1-phenylethylamine (G1)

solketal (G23)

propylene oxide (G30)

0

2-methoxycyclohexanone (G27)

0.021 (OCH₃)

[a] 0: no visible shifting or splitting of signals.

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Design and Evaluation of Inclusion Resolutions

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Figure 1. A PLUTON drawings of the 1:1 inclusion complexes of Taddol 1d with (R)-phenylethylamine and with (S)-phenylethylamine

(in crystals containing 65% S).

Figure 3. A PLUTON drawing of the inclusion complex of Taddol

1j and (S)-lactic acid.

Figure 2. A PLUTON drawing of the inclusion complex of Taddol

1d and (R,R)-trans-2-methoxycyclohexanol (G8).

the guest molecule is hydrogen-bonded to one Taddol with groups are very close to each other. The predominance of

its alcohol function and with its acid function to the other the internal hydrogen bond, that forces the molecules into

Taddol molecule. Additionally, the guest forms an internal a specific shape, is also responsible for a high degree of

hydrogen bond; see Figure 3.

dissymmetry, which could be related to enantioselectivity in

Taken into account that these three guests already give resolutions. Thus, the presence of the strong internal H-

three completely different binding motifs it is clear that any bond should in fact be favourable for resolution processes.

attempt at prediction a priory will be extremely difficult.

Due to the observed similarities in the conformation of the

Lactic Acid Derivatives as Host: Also crystal structure host structures it must be concluded that based on confor-

data of lactic acid derived hosts were studied in some detail, mation alone the compounds cannot be discriminated as

combining newly generated data and literature results. Over “bad” or “good” hosts.

30 inclusion complexes with this type of hosts are known,

A closer inspection of pure host structures with their in-

including our work, but only for 12 structures crystal data clusion structures delivers some interesting results. Host 2a,

are available (see Table 6). Several structure parameters for example, has in the inclusion crystals similar α torsion

were investigated, includingmolecular shape and rigidity, angles as in the pure host lattice, but shows substantial

hydrogen bonding networks and crystal stabilities.

changes in torsion angles β₁and slighter changes in β₂

Conformations of hosts in pure form compared to those (Table 7).

in inclusion complexes were found not to show very large

Obviously, the host molecule is flexible enough to adapt

differences indicating that the conformation of the host its structure somewhat to the included guest. The guest in-

molecules remains similar in most cases despite the higher duces within the limits of the molecular folding a certain

flexibility of these compounds when compared to the Tad- shape for the host structure (Induced Fit). Host 2o (another

dols. In all molecules, with the exception of, 2r, the alcohol good host with 6 reported inclusion complexes), which is

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Table 6. Summary of known crystal structures of lactic acid related hosts

Table 7. Torsion angles of host 2a and its inclusion compounds.

Pure host 2a

Inclusion complexes (mean value)

Standard deviation

Max. angle

Min. angle

α₁

β₁

β₂

–64.27°

53.85°

–45.28°

–58.97°

34.48°

–59.65°

4.01°

24.72°

12.34°

–64.1°

60.11°

–71.61°

–54.9°

12.39°

–47.66°

structurally very similar to 2a, will have the same degree of selectivity of inclusion crystals. A strong hydrogen bond be-

flexibility. However, comparing the crystal structures of the tween host and guest, usually with the host acting as proton

pure host 2r–t and its inclusion compounds it can be seen donor, appears to be essential in most cases. The presence

that in these cases the angles α, β₁and β₂remain almost the of multiple strong intramolecular hydrogen bonds usually

same which is expressed through the small deviation values indicates a poor host, especially if all suitable substituents

(Table 8) compared to the values of host 2a in Table 7. This are involved. It is therefore unlikely that the compounds 2e,

indicates that these hosts have a much higher molecular ri- 2i and 2l–n can act as efficient hosts, as their hydroxy func-

gidity with a diminished possibility to adapt their structure tions are all tied up in intramolecular hydrogen bonds. This

to a guest molecule.

is apparent from the X-ray structures of these compounds,

and an example of this is shown in Figure 4. In the case of

compound 2e a hydrogen bonded dimer is formed, a pattern

which is observed in several of these compounds, pure hosts

as well as in inclusion complexes. However, in this molecule

the second hydroxy function forms a strong intramolecular

hydrogen bond with the o-methoxy group of the aryl func-

tion, thus making it unsuitable for complexating guest com-

pounds via intermolecular hydrogen bond donation. The o-

CF₃-phenyl group of 2i probably leads to the same disad-

vantage.

Table 8. Torsion angles of inclusion compounds of the hosts 2r–t.

Inclusion complexes

Standard

of hosts 2r,s and t

Max. angle Min. angle

deviation

(mean value)

α₁

β₁

β₂

–61.97°

23.40°

–66.03°

2.44°

5.89°

5.03°

–64.18°

32.32°

–57.51°

15.47°

–60.81°

–75.96°

If a guest is included in these hosts it must fit into a more

Further analysis of the available structures of inclusion

rigid framework (lock and key principle). Small molecules, crystals with preferential inclusion of one enantiomer of a

which hardly disturb the formation of the host lattice, can racemate showed that in these cases always an intramolecu-

be included, confirmed by the successful inclusion of sol- lar hydrogen bond directed from the tertiary alcohol to the

vent type molecules only as shown in Table 6.

secondary one is present. Figure 5 shows the X-ray struc-

Hydrogen Bonds: The presence and direction of hydrogen ture of the 1:1 inclusion compound of host 2a and (S)-

bonds is of great importance for the stability and enantio- methyl phenyl sulfoxide, G31, and Figure 6 shows the X-

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Design and Evaluation of Inclusion Resolutions

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Figure 4. PLUTON drawing of the X-ray structure of host 2e show-

ing strong internal hydrogen bonds.

Figure 6. PLUTON drawing of the X-ray structure of the 2:1 in-

clusion compound of host 2a and (R)-3-methylcyclohexanone

(G32).^[21]

ray structure of the 2:1 inclusion compound of host 2a and

(R)-3-methylcyclohexanone (G32). In both complexes the

tertiary alcohol donates its hydrogen to the secondary one,

which in turn acts as donor to complex the guest molecule.

This creates a more rigid system with lower symmetry com-

pared to hosts without such a H-bond system. Without it,

a more flexible host would result, with a lower probability

of imposing enantioselectivity on the included guest. In ef-

fect it removes the pseudo-mirror plain which would other-

wise be present in the host. Thus, the higher degree of rigid-

ity and dissymmetry make it more likely that only one en-

antiomer of a racemate is included preferentially.

Table 9. Available inclusion crystal structures of host 2a and ap-

proximate stability data.

Thus, taken into account the importance of hydrogen

bonds, an analysis of the crystal structures of some poten-

tial hosts reveals why they are unlikely to give inclusion

complexes. In 2f the tertiary alcohol forms a hydrogen bond

to the m-anisyl group of a neighbouringmolecule (see Fig-

ure 7). The overall effect is the same as in 2e (with the o-

anisyl substituent): stabilisation of the crystal structure of

the free host and no hydrogen bonding site available for

external interaction. The methoxy, trifluoromethyl and

chloro substituents in resp. 2g, h, j and k might induce sim-

ilar stabilisation effects.

Figure 5. PLUTON drawing of the X-ray structure of the 1:1 in-

clusion compound of host 2a and (S)-methyl phenyl sulfoxide

(G31).

Crystal stability data, derived from DSC experiments,

The tolyl-substituted hosts 2b–d have found other means

confirm these preliminary conclusions. For host 2a and to stabilize their structures and prevent formation of in-

some of its inclusion complexes the stability of an inclusion clusions. In the case of host 2d a fascinating crystal struc-

crystal is higher than that of the pure host crystal. Also the ture shows that four molecules form a tetramer (see Fig-

inclusion crystal with an optically enriched guest is more ure 8).

stable than a crystal, which includes a racemic guest (see

The hydrophilic alcohol groups are forming a complex

Table 9). All of these inclusion compounds show a similar with each other in the centre of the tetramer and the hydro-

H-bond system. Clearly, for a compound to be suitable as phobic p-tolyl groups are directed outside. Host 2v, where

a host it should have a not too stable crystal structure. Crys- a p-tolyl group replaces the methyl substituent of 2d and

tal structure analysis of the pure host can provide useful the aryl substituents are phenyls, shows a similar effect; now

insights to these aspects.

two molecules form a dimer (see Figure 9), leading to com-

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A. Bruggink et al.

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Figure 9. PLUTON drawing of the X-ray structure of host 2v form-

ing a dimer.^[23]

Figure 7. PLUTON drawing of the X-ray structure of host 2f.

As mentioned before, it may be expected that molecules

with a crystal structure of low stability will be better hosts.

The relative crystal stabilities at room temperature of a

number of (potential) hosts were calculated from melting

points and heats of melting determined by DSC. If the cal-

culated ∆G values are lower or similar to the one of known

good hosts − such as with 2a − inclusion capabilities could

be expected. However, if these values are relatively high it

is less likely that a more stable crystal can be obtained

through inclusion. The results in Table 10 confirm the rela-

tion between the absence of inclusions with compounds 2e,

f, l, and m, and their relatively high stability.

The pure compounds 2b and 2c, and to a lesser degree

2d, however, are less stable than 2a; consequently these

compounds would be expected to be good hosts as well.

The failure of compounds 2b and c to give inclusion com-

pounds remains puzzling. So far no satisfactory explanation

could be found why these compounds do not give any in-

clusion, but in the over 80 attempts made, gel formation

occurred in approximately one third of the cases. This might

be preventing the forming of actual inclusion crystals.

Figure 8. PLUTON drawing of the X-ray structure of host 2d,

forming a tetramer.^[22]

Conclusions

The crystal studies of host and inclusion compounds

parable barriers to formation of inclusion complexes. The proved to be very useful tools to understand the interac-

hydrogen bonds are encapsulated in a polar region between tions between hosts and guests. Successful formation of in-

two host molecules. Although there is still a hydroxy group clusions and resolutions can usually be explained, and also

available for hydrogen bonding to a guest, the formation of the reasons for the lack of success in a great number of

the dimer makes this site sterically less accessible.

candidate host molecules could be determined by examina-

Table 10. Approximate heat of fusion and free heat of fusion values of some pure host compounds.

Hosts

2a

2b

2c

2d

2e

2f

2l

2m

∆H [kJ/mol]

M.p. [K]

∆S [kJ/molK]

∆G₍₂₉₈₎[kJ/mol]

22.6

364.9

0.062

4.425

20.6

348.9

0.059

3.304

22.4

353.9

0.063

3.932

21.9

365.1

0.060

4.31

25.4

371.1

0.068

5.466

33.4

357.6

0.093

6.137

25.9

409.5

0.063

7.432

30.3

384.4

0.079

7.141

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Design and Evaluation of Inclusion Resolutions

FULL PAPER

tion of their crystal structures. Although a number of con- Analysing all literature examples of inclusion resolutions

ditions can be defined for enhancing successful inclusions published by Toda et al. and Weber et al.it becomes clear

(see below) it should be noted that in crystal formation that about 80% of the guests resolved in high enantiomeric

there are always many ways for the molecules involved to excess, act as hydrogen-bond acceptors like ketones, sulfox-

find their own unique path to a stable crystal structure. ides or amines. A certain high degree of dissymmetry is re-

These include the numerous possibilities for formation of quired to allow the formation of two different inclusion

polymorphic structures as recently discussed by Dunitz.^[20]structures with sufficient differences in stability and solubil-

Formation of dimers, trimers or tetramers, inclusion of sol- ity, required for resolution. Experience showed that the use

vents, variation in stoichiometry and many other ways are of liquid guests acting as solvent, increases the chance of

acceptable to reach stable crystal configurations. Rational inclusion crystallisation.

design and predictability are therefore perilous under-

Our results show clearly a decrease in successful forma-

takings. Practice has shown how subtle differences in inter- tion of inclusion compounds in every step moving away

actions in diastereomers can lead to completely different from the Taddol structures. The switch to lactic acid deriva-

crystal structures and huge differences in solubility within a tives already results in a dramatic decrease in resolving abil-

diastereomeric pair. An extreme example is the well known ities. Blocking the secondary alcohol function is not al-

resolution of dl-phenylglycine with camphor sulphonic acid. lowed (see results with 2l–n) whereas adding extra hydrogen

^[24]Nevertheless, the very few successful new inclusion reso- bonding hydroxy groups as in the pantolactones and the

lutions found in our studies and the problems experienced malic acid derivatives opens to many opportunities to reach

in reproducing literature results leads to the conclusion that stable solid phases (gels or crystals) without any inclusion.

the scope of this type of racemate resolution is much more Replacing a hydroxy function by an amine or acylated

limited than initially expected. This is important from an amine moiety has a similar effect. The amine function al-

industrial point of view as well as for more fundamental lows for additional stabilizing hydrogen bonds between the

reasons. It is quite clear that the limitations of resolutions host molecules itself resulting in tenacious gels (as in 5a–k)

through diastereomeric salts cannot be eased through ap- or solids with very low solubility as in the amide series 6.

plying the inclusion approach. A quick testing of a range

All in all it has become clear that inclusion resolutions

of resolving agents and swift formation of crystals as in are of limited scope only and of little use in practical or

Dutch Resolutions is not possible. Salt formation predomi- industrial development of resolutions through selective

nantly enhances chances for stable diastereomeric crystals crystallisation. The energetically favourable ionic interac-

(in which one or both enantiomers of the racemate to be tions in separations through diastereomeric salts precludes

resolved are present by definition), whereas in inclusion res- many alternative crystallisation options compared to when

olutions the partners are left with many choices to reach a this electrostatic factor is absent. In inclusion resolutions

stable end situation, either individually or in combinations. these other options too often frustrate successful enanti-

Given these limitations we can still see some communality omer separations. Some scattered examples using com-

in host structures with favourable properties for inclusions. pletely different host molecules, such as the dipeptide de-

Taking literature results together with our work, over 125 rived from phenylglycine (resolving sulfoxides)^[25], and N-

successful inclusion resolutions using Taddols are currently octylglucamine (resolving Naproxen),^[26]do not effect these

known. Given our extensive experiments it is rather remark- statements.

able that only 5 resulted from our work. To a certain extent

this might be explained by the sometimes structurally very

closely related series of guest racemates used by Toda and

Experimental Section

colleagues. First of all hydrogen bonds are the key factor for

General Remarks:¹H NMR spectra were recorded with a Bruker

success. Given the C₂symmetry in most Taddols directional

AC-100 or with a Bruker AC-300 (300 MHz, FT) spectrometer

effects as with the lactic acid derived examples do not play

with tetramethylsilane as internal standard and the software

WinNMR spectroscopy. IR spectra were run with a Perkin–Elmer

a role. In the latter the direction of the hydrogen bonds is

of special importance for inclusion resolution: internal H-

298, Perkin–Elmer FTIR 1720-X or ATI Mattson Genesis series

bond from the tertiary to the secondary OH, external H-

bond from the secondary OH to the guest molecule. Prefer-

FTIR spectrophotometer using Winfirst as software. Elemental

analyses were performed with a Carlo–Erba instruments CHNSO

ably the host molecules act as H-bond donors. A potential 1108 elemental analyzer. For mass spectroscopy, a double focusing

VG 7070E was used. For the chemical ionisation (CI) technique,

methane was used as reacting gas. GC-separation was carried out

on a fused silica-capillary column (DB-5, 30 m×0.25 mm, film

thickness 0.25 mm). Melting points were measured with a Reichert

Thermopan microscope (uncorrected), a Büchi Melting Point B545

instrument or with a Perkin–Elmer DSC7 instrument. Optical rota-

tions were determined with a Perkin–Elmer 241 polarimeter at

589 nm, equipped with a quartz cell of 1.00-dm path length. The

polarimeter was connected with a thermostat for exact temperature

control and a recorder for continuous optical rotation measure-

host must possess both a definite grade of rigidity, neces-

sary for inclusion and inclusion resolution, but a certain

degree of flexibility allowing an induced fit of a guest is

beneficial. A low stability of the pure host crystals is proba-

bly necessary, as it enhances the possibility that including a

guest will produce a more stable crystal. Inclusion of sol-

vates or poor crystal habits of the host molecules can be

good indicators for formation of inclusion complexes.

Racemic guest compounds should possess a hydrogen

bond forming site (acceptor sites appear to be preferred). ments. GCwas performed with a Hewlett–Packard 5890 or 5890

Eur. J. Org. Chem. 2005, 1082–1096

A. Bruggink et al.

FULL PAPER

Series II instrument, equipped with a capillary HP cross-linked

methyl silicone (25 m×0.31 mm) column, connected to a HP 5890

calculating integrator. Chiral GC was performed using a chiral B-

DEX 120 capillary column (Supelco) or a WCOT Fused Silica

25 m×0.25 mm, CP Chirasil-Dex CB DF 25 m, Varian with H₂as

carrier gas with a HP 6890 instrument. DSC thermograms were

recorded with a Perkin–Elmer DSC7 instrument. Calibration was

performed with In and Zn, Sn or Pb depending on the temperature

range. Samples were prepared by the method described by Jaques,

Collet and Wilen.^[29]Samples were measured in stainless steel large

volume pans (75 mL) or aluminium pans (30 µL) at a rate of 10 °C/

min. HPLC was performed on a Shimadzu 10A VP liquid chroma-

tograph equipped with a reverse phase column by Alltech (Econos-

phere, C8, 5u, 0.46 cm Ø×25 cm), a chiral Daicel Chiralcel OD-H

column (25×0.46 cm, particle size: 5 mm) or a chiral Daicel Chi-

ralcel OB column (25×0.46 cm, particle size: 5 mm) with filtered

hexane/2-propanol mixtures as mobile phase. Detection was at

254 nm and 222 nm and the flow rate was 0.5 mL/min at ambient

temperature. Class VP 5.0 was the software used. Capillary Electro-

phoresis was performed on a HP 3D CE with the software HP 3D

CE-Chemstation. For column chromatography, the flash technique

was used with silica gel 60H (Merck) as stationary phase and a

pressure of about 1.5 bar. Thin-layer chromatograms were run on

glass-supported silica gel 60 plates (0.25-layer, F₂₅₄, Merck). Com-

pounds were detected using UV and oxidizing reagents, i.e. 5%

H₂SO₄in ethanol or a mixture of (NH₄)₆Mo₇O₂₄⋅4H₂O (21 g),

(NH₄)₄Ce(SO₄)₄⋅2H₂O (1.8 g), water (469 mL) and 97% H₂SO₄

(31 mL). Dry solvents were obtained as follows: Dichloromethane

was distilled from phosphorus pentoxide. Diethyl ether was pre-

dried with calcium chloride and distilled from calcium hydride.

Hexane and benzene were distilled from calcium hydride. Triethyl-

amine and phenylethylamine were distilled from potassium hydrox-

ide. Tetrahydrofuran was distilled from lithium aluminium hydride

and ethyl acetate from potassium hydrogen carbonate. All other

solvents and reagents were either p.a. or technical quality and used

as obtained from the supplier.

lysed for the presence of the respective guest compound by ¹H

NMR analysis. If an inclusion complex was obtained, the ee of the

guest included was determined. (see also below).

General Procedure for Crystallisation Experiments Under High

Pressure: The pure Taddols were dissolved together with the respec-

tive guest compound in heptane and then filtered. The experiments

were executed in a host/guest ratio of 1:1 at room temperature using

15 kbar of pressure for five hours.

General Procedure for Crystallisation Experiments with Individual

Taddols: The Taddol was dissolved in the liquid racemic guest com-

pounds while boiling. The mixtures were cooled to room tempera-

ture and filtered. In those cases in which crystals were obtained,

they were filtered off, washed with heptane and analysed for the

presence of the respective guest compound by ¹H NMR analysis.

If an inclusion complex was obtained, the ee of the guest included

was determined.

Procedure for Vapour Sorption Experiment: Racemic guest com-

pound (i.e. phenylethylamine) was heated in a flask to 110 °C while

powdered Taddol was kept in a small tube inside the flask, sepa-

rated from the liquid amine. After 30 min the test tube was removed

and analysed for the presence and the ee of included phenylethyla-

mine.

Procedure for Grinding Experiment: Taddol and racemic guest (i.e.

phenylethylamine) were mixed and ground in a mortar for 20 min-

utes. Solid host and liquid guest were combined in a ratio of 1:1

or 1:2. The solid was then washed with heptane and analysed. In-

clusion complexes, when formed, were treated and analysed as

above.

General Procedure for Crystallisation Experiments with Mixtures of

Taddols: Various mixtures of the Taddols were dissolved with the

respective guest compound in hexane/ toluene (1:1) or heptane and

then filtered. They were used in a host/guest ratio of 1:1. Work-up

and analysis of obtained crystals was as above.

Synthesis of Host Compounds: All host compounds were prepared

according to known procedures. The starting hydroxy or amino

acid was esterified using thionyl chloride in methanol, followed by

arylations with a Grignard reagent or aryllithium derivative. Acyl-

ation of amino alcohols could efficiently be done using acid chlo-

rides and standard Schotten–Baumann procedures. No O-acylation

was observed. Most taddols, 1a–l, were purified through

chromatography followed by crystallisation. The host compounds

derived from lactic acid, malic and amino acids could be purified

by crystallisation only. Full details are available as Supporting In-

formation (for Supporting Information see also the footnote on the

first page of this article).

General Procedures for ee Determination; Derivatisation with Ben-

zoyl Chloride: Equal amounts of guest compound, benzoyl chloride

and NaHCO₃were mixed for 20 min. Then a few mL heptane were

added and the reaction mixture was stirred for another 20 minutes.

After filtration, the solvent was evaporated and the residue ana-

lysed for ee (see Table below).

Derivatisation with Camphonyl Chloride: Guest compound

(5 mmol) was stirred in 25 mL of pyridine at 0 °C while 1.36 g

(6 mmol) camphonyl chloride was added slowly. After stirring over-

night, 2 mL MeOH were added and the solvents evaporated. After

dissolving in 100 mL CH₂Cl₂, the product was washed with H₂O,

1 m NaHCO₃and H₂O, dried and analysed for ee (see Table 11).

Guest Compounds: Racemic or optically pure guest compounds

were obtained from regular commercial sources and purified and

analysed were appropriate, using general methods shown below.

Supporting Information: Experimental details and properties of the

tartaric acid, lactic acid, and amino acid derivatives are available

as Supporting Information. Details of the crystal data and data

collection of the complex 1d with (R), (S), and racemic phen-

ethylamine, the complex of 1d with (S,S)-trans-2-methoxycy-

clohexanol, the complex of 1j with (S)-lactic acid, the complex of

2a with (S)-methyl phenyl sulfoxide, and the compounds 2e and 2v

are also available.

General Procedures for Inclusion Resolutions: Several experimental

techniques were used to reach successful crystallisation in resolu-

tions, including all common methods and tricks to induce nucle-

ation and crystal formation. A representative selection is given be-

low, using the Taddols as example.

General Procedure for Crystallisation Experiments with Individual

Taddols in Solvent: The pure Taddols were dissolved together with

the respective guest compound in hexane/toluene (1:1) or heptane

and then filtered. Most experiments were executed in a host/guest

ratio of 1:1 at room temperature. In those cases in which crystals

were obtained, they were filtered off, washed with heptane and ana-

X-ray Crystallographic Study: Crystallographic data for the struc-

tures described in this paper are available:

(4R,5R)-4,5-Bis[bis(4-methylphenyl)hydroxymethyl]-2,2-dimethyl-

1,3-dioxolane (1d), complex with (R)-1-phenylethanamine (G1)

(1:1); see Figure 1; CCDC-246184.

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Design and Evaluation of Inclusion Resolutions

FULL PAPER

Table 11. Methods applied to determine the ee.

ee Determination method

can be applied to

A

B

C

D

E

F

G

H

I

camphonyl chloride derivatisation, chiral GC, β-CD

optical rotation

R1,R3–5

R2,R6,R9–10,R15–R17,R21–R23,R25–R30

R7,R11

R8

R12

R13

R14,R18

R19

R20

benzoyl chloride derivatisation, chiral HPLC, OD-H

1

camphonyl chloride derivatisation, H NMR

chiral HPLC, OD-H

benzoyl chloride dervatisation, chiral HPLC, OB

chiral GC, β-CD

benzoyl chloride derivatisation, chiral GC, β-CD

diazomethane derivatisation, chiral GC, β-CD

chiral HPLC, OB

J

R24

[6] a) T. Vries, H. Wynberg, E. van Echten, J. Koek, W. ten Hoeve,

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S. van der Sluis, L. A. Hulshof, J. H. M. H. Kooistra; Angew.

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(4R,5R)-4,5-Bis[bis(4-methylphenyl)hydroxymethyl]-2,2-dimethyl-

1,3-dioxolane (1d), complex with (S)-1-phenylethanamine (G1)

(1:1); see Figure 1; CCDC-246185.

(4R,5R)-4,5-Bis[bis(4-methylphenyl)hydroxymethyl]-2,2-dimethyl-

1,3-dioxolane (1d), complex with (rac)-1-phenylethanamine (G1)

(1:1); CCDC-246186.

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J. W. Nieuwenhuijzen, R. F. P. Grimbergen, C. Koopman,

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(4R,5R)-4,5-Bis[bis(4-methylphenyl)hydroxymethyl]-2,2-dimethyl-

1,3-dioxolane (1d), complex with (1R,2R)-2-methoxycyclohexanol

(G8) (2:1); see Figure 2; CCDC-246187.

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(2R,3R)-2,3-Bis[bis(4-methylphenyl)hydroxymethyl]-1,4-dioxa-

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(S)-1,1-Bis(2-methoxyphenyl)propane-1,2-diol (2e); see Figure 5;

CCDC-246189.

(S)-1,1-Diphenylpropane-1,2-diol (2a), complex with S-methyl

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(S)-1,1-Bis(3-methoxyphenyl)propane-1,2-diol (2f); see Figure 8;

CCDC-246191.

[11] F. Toda, Top. Curr. Chem. 1987, 140, 43.

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CCDC-246184 to -246191 contain the supplementary crystallo-

graphic data for this paper. These data can be obtained free of

charge from The Cambridge Crystallographic Data Centre via

www.ccdc.cam.ac.uk/data_request/cif.

.

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Acknowledgments

We would like to acknowledge the valuable contributions of our

colleagues in the Dutch Resolution project: Dick Kellogg, Jan Dal-

molen, Ton Vries, Jose Nieuwenhuijzen, Marcel van der Sluis, Kees

Pouwer, Imre Markowitz, Joanne Loh, Reinier Grimbergen, Wil-

lem van Enckevort, Elias Vlieg, Henk Hiemstra, Bert Hulshof and

Claire Gervais.

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Miyamoto, M. Sakamoto, K. Yoshioka, R. Takaoka, F. Toda,

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H. Takahashi, K. Nakamura, N. Azuma, F. Toda, K. Endo,

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Received: August 30, 2004

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Design and evaluation of inclusion resolutions, based on readily available host compounds

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