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. Author manuscript; available in PMC: 2015 Jan 14.
Published in final edited form as: Tetrahedron Asymmetry. 2006 Oct 27;17(19):2821–2832. doi: 10.1016/j.tetasy.2006.10.014

Enantiomeric impurities in chiral synthons, catalysts, and auxiliaries. Part 3

Ke Huang 1, Zachary S Breitbach 1, Daniel W Armstrong 1,*
PMCID: PMC4294700  NIHMSID: NIHMS14312  PMID: 25598583

Abstract

The enantiomeric excess of chiral reagents used in asymmetric syntheses directly affects the reaction selectivity and product purity. In this work, 84 of the more recently available chiral compounds were evaluated to determine their actual enantiomeric composition. These compounds are widely used in asymmetric syntheses as chiral synthons, catalysts, and auxiliaries. These include chiral alcohols, amines, amino alcohols, amides, carboxylic acids, epoxides, esters, ketones, and oxolanes among other classes of compounds. All enantiomeric test results were categorized within five purity levels (i.e. <0.01%, 0.01% to 0.1%, 0.1% to 1%, 1% to 10%, and >10%). The majority of the reagents tested were determined to have enantiomeric impurities over 0.01%, and two of them were found to contain enantiomeric impurities exceeding the 10% level. The most effective enantioselective analysis method was a GC approach using a Chiraldex GTA chiral stationary phase (CSP). This method worked exceedingly well with chiral amines and alcohols.

1. Introduction

Enantioselective reactions are of great importance to chemists involved in asymmetric synthesis. The enantiomeric purity of a product is affected by 3 factors: 1) the enantioselectivity of the reaction; 2) the enantiomeric excess of the starting material and/or the catalyst/auxiliary used; and 3) the susceptibility for the desired product to racemize, especially during work-up or storage. Previously, we found detectable amounts of enantiomeric impurities in 192 commercial chiral compounds.1, 2

These compounds are widely employed in asymmetric syntheses as chiral catalysts/catalyst ligands, synthons/synthetic building blocks, chiral auxiliaries and chiral resolving agents. New chiral compounds, catalysts, auxiliaries and synthons are continually being developed, the most useful of which are made available commercially. Herein, we examine new chiral compounds that have not been assayed previously and/or have been introduced after 1999, when the last comprehensive evaluation of commercial chiral compounds was reported.2 When enantiomerically impure compounds are employed in asymmetric synthesis, especially in the pharmaceutical industry, the underestimated contaminants will introduce various amounts of enantiomeric impurities in the “single-enantiomer” reaction and products. In biological processes, these undesired enantiomeric byproducts usually show different effects and/or different pharmacokinetics/pharmacodynamics and thus have different therapeutic values.3 Although the stereoselectivity of asymmetric synthetic processes continue to improve, an awareness of the enantiomeric composition of chiral reagents being used remains essential.

2. Results and Discussion

Of the 84 chiral compounds tested, 85 % of them were separated via enantioselective GC, and of these, 54 % were best separated on the Chiraldex GTA column. This is due to the fact that many of the compounds in this study were chiral amines and alcohols which, when trifluoroacetylated, gained distinct enantioselective interactions with the trifluoroacetylated chiral stationary phase of the GTA column.4 Also, the GTA chiral stationary phase showed impressive separating capabilities for ketones, epoxides, and halogenated acids. Examples of these include the separations of 3-methylcyclopentanone, epoxybutane, and chloropropionic acid, respectively.

Other effects of the trifluoroacetylation of free alcohols and amines include altered enantioselectivity, increased analyte volatility, faster analysis time, improved peak shape, and increased efficiency. Figure 1 illustrates some of these properties in the GC enantiomeric separations of derivitized (Fig 1A and B) and native (Fig 1C and D) ethyl-4-chloro-3-hydroxybutyrate. Peaks A and D represent the (S)-(−) enantiomer while peaks B and C represent the (R)-(+) enantiomer. Both enantiomeric separations have comparable baseline separations with resolutions greater than two. However, a comparison of the separation of the native analyte versus its trifluoroacetyl derivative (Figure 1) shows that the analysis time for the derivative is shorter and the peaks are sharper (which makes the detection and quantitation of enantiomeric impurities much easier). Furthermore, the reversal of the elution order of the two enantiomers prior to, and after, derivatization indicates that the introduction of the trifluoroacetyl group alters the separation mechanism. It has also been reported that acetic anhydride, chloroacetic anhydride, dichloroacetic anhydride, and trichloroacetic anhydride may be used for this same purpose.5

Figure 1.

Figure 1

GC enantiomeric separations of derivatized (A and B) and native (C and D) ethyl-4-chloro-3-hydroxybutyrate. Peaks A and D represent the (S)-(−)-enantiomer and peaks B and C represent the (R)-(+) enantiomer. Helium carrier gas, G-TA column, 120°C, FID.

Table 3 lists all chiral compounds examined in this study, as well as, references describing their use in asymmetric syntheses. The separation conditions for each compound assayed are listed in Table 1 and Table 2. Also, Table 3 indicates the actual enantiomeric composition of each compound and the technique used to determine this composition. As shown in Figure 2, 82% of the compounds analyzed were found to contain enantiomeric impurities over 0.01%. Only 8% of the compounds contained enantiomeric impurities between 0.01%–0.1%, whereas, 46% of the samples had enantiomeric impurities in the level 0.1%–1%, and 25% of the samples displayed enantiomeric impurities in the range of 1%–10%. Two compounds were found with enantiomeric contaminants over 10%.

Table 3.

The enantiomeric excess of the organic synthesis reagents

Use in Asymmetric Synthesis and
References
Name and Structure of Chiral
Compound
Enantiomeric Composition Method
Numberb
%enantiomeric
contaminant
enantiomeric
excess (e. e.)a
Synthons or Chiral building blocks
  1. Development and synthesis of 2-o-methylcytidine24

  2. Synthesis of amide analogs of the cannabinoid CB1 receptor antagonist25

2-Aminoheptane
graphic file with name nihms14312t1.jpg
(S)=0.09 *99.83 (R) GC-1
(R)=0.35 99.31 (S)
2-amino-3-thiazolidine derivatives as nitric oxide synthase inhibitors27, 28 (S)=0.07 *99.87 (R) GC-2
(R)=0.09 99.82 (S)
  1. Enantioselective acylation29

  2. Synthesis of a new class of nitric oxide synthase inhibitor, 4, 5 disubstituted-1,3-oxazolidin-2-imin e derivatives30

2-Amino-1-pentanol
graphic file with name nihms14312t2.jpg
(S)<0.01 *>99.99 (R) GC-3
(R)<0.01 >99.99 (S)
  1. Synthesis of crystalline chellates31

  2. Preparation of imidazo[1,2-b]pyridazines under Swern oxidative conditions32

2-Amino-1-phenyl-1, 3-propanediol
graphic file with name nihms14312t3.jpg
(S,S)=0.52 *98.97 (R,R) GC-4
(R,R)=0.06 >99.89 (S,S)
  1. Stucture –activity relationship study of 1H-imidazo [4,5-c]quinolines that induce interferon production33

  2. Preparation of 2′-aldehyde oligonucleotides for chemoselective ligation study34

3-Amino-1, 2-propanediol
graphic file with name nihms14312t4.jpg
(S)=0.28 99.44 (R) GC-5
(R)=0.93 *98.14 (S)
Synthesis of antitumor agent35, 36 3-Aminopyrrolidine
graphic file with name nihms14312t5.jpg
(S)=0.66 98.67 (R) GC-5
(R)=0.17 *99.67 (S)
Potential human dopamine D4 antagonists synthesis37 1-Benzyl-3-aminopyrrolidine
graphic file with name nihms14312t6.jpg
(S)=0.17 *99.67 (R) GC-6
(R)<0.01 >99.99 (S)
  1. Preparation of Evans Auxiliary38, 39

  2. Chemoenzymatic synthesis of the polyketide macrolactone10-deoxymethynolide40

  3. Asymmetric total synthesis of (+)-migrastatin, a potent cell migration inhibitor41

4-Benzyl-3-propionyl-2-oxazolidinone
graphic file with name nihms14312t7.jpg
(S)=0.37 99.26 (R) GC-7
(R)<0.01 *>99.99 (S)
Ring-closing metathesis to cyclic sulfamide peptidomimetics42 Bis (α-methylbenzyl)sulfamide
graphic file with name nihms14312t8.jpg
(S)=6.49 *87.03 (R,R) GC-8
(R)=3.29 93.43 (S,S)
  1. Starting material of chiral diamine-chelated aryllithiums 43

  2. Synthesis of a novel arylpiperazine as potent and selective agonist of the melanocortin subtype-4- receptor44

  3. Fast microwave promoted palladium-catalyzed synthesis of Phthalides45

2-Bromo-α-methylbenzyl-alcohol
graphic file with name nihms14312t9.jpg
(S)=0.36 *99.29 (R) GC-9
(R)=0.14 99.73 (S)
  1. Synthesis of 2, 3-diminopyridine bradykinin B1 receptor antagonists46

  2. Preparation of substituted N-(arylmethyl)aryloxy arylcarboxamide antagonists for the PGE2 receptor EP447

1-(4-Bromophenyl)ethylamine
graphic file with name nihms14312t10.jpg
(S)=0.24 *99.53 (R) GC-10
(R)=0.42 99.16 (S)
  1. Total synthesis of 17,18,19,20-d4-iPF2a-III 32, for animal metabolism studies48

  2. Synthesis of kinsenoside and goodyeroside A49

  3. Control of regioselectivity of the pivalaldehyde acetalization50

1,2,4-Butanetriol
graphic file with name nihms14312t11.jpg
(S)=0.84 *98.33 (R) GC-5
(R)<0.01 >99.99 (S)
Synthesis of 1,2-dihdroxyimino-3,7-di-aza-9,10- O-iso-propylidene decane, a vic-dioxime derivative for its metal complex study51 4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane
graphic file with name nihms14312t12.jpg
(S)=0.12 99.76 (R) GC-11
(R)=0.28 *99.45 (S)
  1. Used as substrates in transesterification of vinyl esters52

  2. Lanthanide (III) triflate-catalyzed thermal and microwave-assisted synthesis of benzyl ethers53

  3. Synthesis of 3-phenoxypropyl piperidine analogues as ORL1 receptor agonists54

  4. Preparation of fluoxetine analogues, a novel class of anti-candida agents55

3-Chloro-1-phenyl-1-propanol
graphic file with name nihms14312t13.jpg
(S)=0.39 *99.22 (R) GC-12
(R)=0.24 99.53 (S)
  1. Synthesis and structure-activity relationship study of ethacrynic acid analogues on glutathione-s-tranferase P1-1 inhibition56

  2. Synthesis of a peroxime proliferator activated receptor (PPAR) α/γ agonist57

Chloropropionic acid
graphic file with name nihms14312t14.jpg
(S)=2.79 *94.42 (R) GC-5
(R)=0.38 99.25 (S)
  1. Synthesis of C1–C11 fragment of bafilomycin A158

  2. Used in DMF promoted xylosylation of terpenols59

  3. Total synthesis of brasoside and littoralisone60

  4. Synthesis of marine sponge alkaloid hachijodine B61

  5. Stereoselective synthesis of Fusarium toxin equisetin, a potent

β-Citronellol
graphic file with name nihms14312t15.jpg
(S)=1.38 *99.42 (R) GC-13
(S)<0.01 >99.99 (R)
  1. Study of a new method to oxidize primary alcohols to carboxylic acids63

  2. Study of the influence of the nature of chiral auxiliaries on the diasteroselective hydrogenation of o-methoxy benzoic acid64

  3. Used in the study of reductive alkylation of aromatic carboxylic acid derivatives65

1-(2-Methoxybenzoyl)-2-Pyrolidinemethanol
graphic file with name nihms14312t16.jpg
(S)<0.01 >99.99 (R) LC-1
(R)<0.01 >*99.99 (S)
  1. Preparation of chiral crown ethers6668

  2. Starting material for the synthesis of (3R,4S)-3,4-dihydroxy-5-oxohexyl phosphonic acid69

  3. Synthesis through Mitsunobu reacion of chiral diesters and chiral diamines as macrocylic frameworks70

2,3-O-Benzylidene-D-threitol
graphic file with name nihms14312t17.jpg
(−)=0.20 *99.60 (+) GC-14
(+)=7.42 85.16 (−)
Synthesis of lower alkyl 4-cyano-3-hydroxybutyrates71 Ethyl-4-bromo-3-hydroxybutyrate
graphic file with name nihms14312t18.jpg
(S)=0.37 99.26 (R) GC-15
(R)=0.36 *99.29 (S)
  1. Substrate for enzymatic ammonolysis72

  2. Synthesis of 4-cyano-3-hydroxybutyric acid esters73

  3. Preparation of epoxybutanoic acid esters74

Ethyl-4-chloro-3-hydroxybutyrate
graphic file with name nihms14312t19.jpg
(S)=0.49 *99.02 (R) GC-15
(R)=0.04 99.93 (S)
  1. Alkanol absolute configuration study with cyclopenta[b]furan derivative75

  2. Ruthenium-catalyzed quinoline synthesis through 2-aminobenzyl alcohol cyclization with secondary alcohols76

  3. Parallel carbonylation of aryl halides77

  4. Palladium-catalyzed heteroannulation of bromobenzylaldehyde78

  5. Enzymatic synthesis of aroma compound xylosides via transfer reaction79

2-Heptanol
graphic file with name nihms14312t20.jpg
(S)=0.12 *99.77 (R) GC-16
(R)=1.32 97.36 (S)
Synthesis of analogs of antitumor agents for action mechanism study of XK469 and SH8080, 81 2-(4-Hydroxyphenoxy) propionic acid
graphic file with name nihms14312t21.jpg
(S)<0.01 >99.99 (R)c LC-2
  1. Starting material for the synthesis of a new class of antiatherosclerosis agents, the NO-donor antioxidants82

  2. Buiding block for novel potent inhibitors of lipid peroxidation with protective effects against reperfusion arrhythmias83

  3. Synthesis of CX-659S and its related compounds for the study of their effects on hypersensitivity reaction84

  4. Vitamin E precursor85

6-Hydroxy-2,5,7,8-tetramethyl- chroman-2-carboxylic acid
graphic file with name nihms14312t22.jpg
(S)<0.01 >99.99 (R) LC-3
(R)<0.01 >*99.99 (S)
  1. Substrate for enantiomerically pure 4 or 5 substituted lactones86

  2. Study of oxidation of cyclic ketones by CH3ReO3/H2O2 catalytic system in room temperature ionic liquids through Baeyer–Villiger reaction87

  3. Synthesis of 3,4-bridged 1, 6, 6aλ4-trithiapentalenes88

3-Methylcyclopentanone
graphic file with name nihms14312t23.jpg
(S)=0.10 99.80 (R)c GC-17
  1. Synthesis of the 5-HT3 receptor probe89

  2. Fullerene substitution with piperazine90

  3. Preparation of 1, 4-benzothiazine analogues, thymocyte apoptosis and thymus inducers91

2-Methylpiperazine
graphic file with name nihms14312t24.jpg
(S)=0.13 *99.75 (R) GC-6
(R)=0.15 99.71 (S)
Synthesis of 10-azaprostaglandinE192 5-Oxo-3-pyrrolidinecarboxylic acid ethyl ester
graphic file with name nihms14312t25.jpg
(S)<0.01 *>99.99 (R) GC-18
(R)=0.62 98.76 (S)
Efficient Synthesis of Cyclopentenones from Enynyl Acetates93 1-Octyn-3-ol
graphic file with name nihms14312t26.jpg
(S)=0.20 *99.61 (R) GC-19
(R)=0.17 99.77 S)
  1. Preparation of prochiral phosphinic acid derivatives for the synthesis of P-Stereogenic phosphinates94

  2. Synthesis of a methyl ketone as a substrate for samarium (II)-promoted aromatic ring spirocyclization95

4-Penten-2-ol
graphic file with name nihms14312t27.jpg
(S)=1.11 *97.79 (R) GC-13
(R)=0.39 99.22 (S)
  1. Starting material for the synthesis of 1-arylmethyl-3-(1-methyl-2-amino) ethyl-5-aryl-6-methyluracils, a new class of small molecule GnRH antagonists96

  2. Preperation of tri- and tetra-substituted ureas as a novel class of steroid mimics97

3-Pyrrolidinol
graphic file with name nihms14312t28.jpg
(S)=0.04 99.92 (R) GC-20
(R)=0.54 *98.92 (S)
Used in the study of enantioselective palladium(II)-catalyzed aerobic Alcohol oxidations with(−)-sparteine98, 99 α-(Trifluoromethyl) benzyl alcohol
graphic file with name nihms14312t29.jpg
(S)=1.06 97.88 (R) GC-2
(R)=1.32 *97.36 (S)
Important synthetic component of ferroelectric liquid crystals100 1,1,1-Trifluorooctan-2-ol
graphic file with name nihms14312t30.jpg
(S)=0.90 98.20 (R) GC-21
(R)=0.56 *98.88 (S)
Catalyst/catalyst ligands
Solid support catalysis for hydrosilylation of ketones101 2-Amino-1, 2-diphenylethanol
graphic file with name nihms14312t31.jpg
(1S,2R)<0.01 *>99.99 (1R,2S) GC-22
(1R,2S)<0.01 99.60 (1S,2R)
Solid support catalysis for hydrosilylation of ketones101 2-Amino-3-methyl-1-butanol
graphic file with name nihms14312t32.jpg
(S)=0.23 *99.54 (R) GC-3
(R)=0.74 98.52 (S)
Solid support catalysis for hydrosilylation of ketones101 2-Amino-1-phenylethanol
graphic file with name nihms14312t33.jpg
(S)=2.15 *95.70 (R) GC-20
(R)=3.17 93.66 (S)
  1. High throughput ruthenacycle-catalyzed asymmetric transfer hydrogenation102

  2. Enantiotopic lithiation of prochiral benzamide chromium complex103

  3. Used in asymmetric addition of silane to cyclohexanone104

  4. Asymmetric synthesis of (+)-anatoxina105

Bis (α-methylbenzyl)amine
graphic file with name nihms14312t34.jpg
(S)<0.01 *>99.99 (R) LC-4
(S)=0.61 98.79 (S)
  1. HBr scavenger to increase the yield of photoinduced addiction reaction product of 1,4-dibromo-2,5-piperazinedione and 1-alkenes106

  2. Exchange reactions of ethylene oxides and Et2CH2CHROH107

Epoxybutane
graphic file with name nihms14312t35.jpg
(S)=0.13 99.74 (R) GC-23
(R)=0.01 *99.98 (S)
Accelerators for hydrosilation of unsaturated organic compounds108 1-Phenyl-2-propyn-1-ol
graphic file with name nihms14312t36.jpg
(S)=2.02 95.96 (R) GC-24
(R)=0.15 *99.70 (S)
Chiral auxiliaries
Asymmetric alkynylation of aromatic ketones109 2-Amino-1,1-diphenyl-1-propanol
graphic file with name nihms14312t37.jpg
(S)=1.26 *97.49 (R) LC-5
R<0.01 >99.99 (S)
  1. Synthesis of (S)-fontalin and its antipode110

  2. Synthesis of malyngolide, a marine antibiotic111

  3. Synthesis of sarcophytol A, an anticarcinogenic marine cembranoid112

2-(Anilinomethyl)pyrrolidine
graphic file with name nihms14312t38.jpg
(S)=9.18 *81.64 (R) LC-6
(R)=4.98 90.04 (S)
Scholkopf chiral auxiliary 113117 2,5-Dihydro-3,6-dimethoxy-2-iso propylpyrazine
graphic file with name nihms14312t39.jpg
(S)=4.59 *90.83 (R) GC-11
(R)=2.37 95.26 (S)
  1. Synthesis of α-(1-methylethyl)-α-(3-oxopropyl) benzeneacetonitriles118

  2. Chiral resolution of 6-phenyl-4-phenylethynyl-1,4-dihy dropyridines, A3 adenosine receptor antagonists119

2,2-Dimethyl-1,3-dioxolane-4-methanol
graphic file with name nihms14312t40.jpg
(S)=2.23 95.55 (R) GC-25
(R)=2.40 *95.21 (S)
NMR configuration assignment of α-carboxylic acids120 1-Indanol
graphic file with name nihms14312t41.jpg
(S)=13.8 *72.50 (S) LC-7
(R)=11.1 77.80 (R)
Dynamic kinetic resolution of α bromoesters121 Lactamide
graphic file with name nihms14312t42.jpg
(S)=1.10 *97.80 (R) GC-15
(R)=1.12 97.77 (S)
a

The first eluted peaks are indicated with the sign *.

b

GC=gas chromatography, LC=liquid chromatography (here high pressure chromatography). Each method is taken from Table 1 and Table 2 where the specific condition for each separation is listed

c

For these two compounds, only one enantiomer is tested because the other enantiomer is not commercially available.

Table 1.

Enantioselective methods by gas chromatography (GC)

GC Method Number a Column b Length (m) Temperature (°C) flow rate (ml/min)
GC-1 Chiraldex G-PN 20 110 1
GC-2 Chiraldex G-TA 30 110 1
GC-3 Chiraldex G-PN 20 100 1
GC-4 Chiraldex G-TA 30 115 1
GC-5 Chiraldex G-TA 30 100 1
GC-6 Chiraldex G-TA 30 130 1
GC-7 Chiraldex B-DM 20 130 1
GC-8 Chiraldex G-TA 30 110 1
GC-9 Chiraldex B-DM 20 150 1
GC-10 Chiraldex G-BP 20 135 1
GC-11 Chiraldex B-DM 20 90 1
GC-12 Chiraldex B-DM 20 140 1
GC-13 Chiraldex G-TA 30 60 1
GC-14 Chiraldex G-TA 30 140 1
GC-15 Chiraldex G-TA 30 120 1
GC-16 Chiraldex G-TA 30 65 1
GC-17 Chiraldex G-TA 30 50 1
GC-18 Chiraldex G-TA 30 160 1
GC-19 Chiraldex B-DM 20 80 1
GC-20 Chiraldex G-TA 30 150 1
GC-21 Chiraldex B-TA 20 100 1
GC-22 Chiraldex G-BP 20 140 1
GC-23 Chiraldex G-TA 30 35 1
GC-24 Chiraldex B-DM 20 125 1
GC-25 Chiraldex G-TA 30 80 1
a

Is used to identify the Seperation techniques in Table 3. Every analyte with amino or hydroxyl functional groups was derivatized with trifluoroacetic anhydride to help with the selectivity of separation and the volatility of analytes (see experimental section)

b

Is the abbreviation for the GC columns used. All the full names can be looked up in the experimental section.

Table 2.

Enantioselective methods by gas chromatography (GC)

HPLC Method Number a Column b Mobile Phase c (%, v/v) Flow Rate (ml/min)
LC-1 Chirobiotic T2 H2O:TEAA=100:0.1, pH 4.1 0.25
LC-2 Chirobiotic T2 ACN: HOAc: TEA=100:0.15:0.15 1
LC-3 Poly-DPEDA Heptane: IPA: TFA=95:5:0.1 0.25
LC-4 Cyclobond I 2000 AC H2O:TEAA=100:0.1, pH 4.1 1
LC-5 Cyclobond I 2000 AC H2O:TEAA=100:0.1, pH 4.1 1
LC-6 Cyclobond I 2000 AC H2O:TEAA =100:0.3, pH 4.1 (0 °C) 0.25
LC-7 Cyclobond I 2000 DM H2O:TEAA:CH3OH=97:0.1:3, PH=7.1 1
a

is notation is used to identify the separation techniques in Table 3

b

is the abbreviation for the HPLC columns used. All the full names can be looked up in the experimental section.

c

Mobile phase: ACN=acetonenitrile; TEAA=triethylamine acetate; HOAc=acetic acid

Figure 2.

Figure 2

Comparison of results obtained in this study (2006) and results obtained in prior work (1998–99)

Figure 2 also shows a direct comparison of the level of enantiomeric contaminants found in the chiral compounds assayed in this study with those that were tested in 1998–99. In both studies, 2% of the chiral compounds tested contained enantiomeric impurities greater than 10%. However, the greatest enantiomeric impurity for any chiral compound was found in the 1998 analysis of (R)-tert-butyl-4-formyl-2, 2-dimethyl-3-oxazolidine, which was determined to contain 15.11% of the (S)-enantiomer. This is just slightly higher than the 13.80% maximum enantiomeric impurity found in (R)-1-indanol during this study. Figure 2 also shows that within the enantiomeric impurity ranges of 1–10% and 0.1–1%, the results of the two studies are fairly comparable with the abundances in this study being just slightly higher. The major difference in reagent purity in the studies is in the 0.01–1% and <0.01% ranges. The number of very high enantiomeric excess compounds found in this study approached 20%, whereas few, if any, chiral compounds of these purities were available prior to 1998–99. However, there were a higher percentage of compounds in the 0.01–1% range in previous studies.

It was also observed that two enantiomeric compounds will not necessarily contain comparable amounts of enantiomeric impurities. This trend is best observed with the assay of 2, 3-O-benzylidene-D-threitol. The (+)-enantiomer had an enantiomeric excess of 85.16%, while the much more pure (−)-enantiomer had an enantiomeric excess of 99.60%. This determination is consistent with findings in other studies.1, 2

Given the results of this and previous studies, it is apparent that further improvements in the enantiomeric purities of reagents used in asymmetric synthesis would be beneficial. This can be achieved through further refinements in the manufacture and purification of most of these chiral reagents. Since novel chiral compounds are constantly being developed and added to the repertoire of synthetic organic chemists, 621 some knowledge as to their enantiomeric composition and the availability of facile methods for their analysis will remain important.

3. Experimental

3.1 Materials

All HPLC columns (25 cm × 4.6 mm i. d.) and GC columns (10 m × 0.25 mm, 20 m × 0.25 mm, 30 m × 0.25 mm) were obtained from Advanced Separation Technologies, Inc. (Whippany, NJ). The LC columns used were Cyclobond I 2000 AC (acetylated-β-cyclodextrin), Cyclobond I 2000 DM (dimethylated-β-cyclodextrin), Chirobiotic T2 (teicoplanin), and Poly-DPEDA (poly N,N′-[(1R, 2R)-1,2-diphenyl-1,2-ethanediyl] bis-2-propenamide).22 GC analysis was performed using Chiraldex B-DM (di-O-methyl-β-cyclodextrin), Chiraldex G-PN (2, 6-di-O-pentyl-3-propionyl-γ-cyclodextrin), Chiraldex G-BP (2, 6-di-O-pentyl- 3-butyryl-γ-cyclodextrin), Chiraldex G-TA (2, 6-di-O-pentyl-3-trifluoroacetyl-γ-cyclodextrin) columns and Chiraldex B-TA(2, 6-di-O-pentyl-3-trifluoroacetyl- β-cyclodextrin).

Trifluoroacetic anhydride (99+ %) was from Aldrich (Milwaukee, WI). Trifluoroacetic acid was obtained from Fisher Scientific (St Louis, MO). The water used, was deionized and purified with a Synery 185, Millipore filter. All the mobile phases were degassed with a VWR Model 250HT sonicator before HPLC analyses. All the chiral compounds examined in this paper were obtained from Aldrich.

3.2 Apparatus and methods

All HPLC separations were performed on the following Shimadzu (Columbia, MD) instrumentation: two LC-6A pumps; a SPD-6A UV spectrophotometric detector; a SCL-10A system controller; and a CR 601 Chromatopac integrator. All compounds were dissolved in acetonitrile and the wavelength of detection was 254 nm. Most of the compounds were tested with a flow rate of 1 ml/min at ambient temperature (25°C). Lower flow rate was used for 2-(Anilinomethyl) pyrrolidine, 6-hydroxy-2, 5, 7, 8- tetramethyl-chroman-2-carboxylic acid and 1-(2-methoxybenzoyl)-2-pyrrolidinemethanol to increase peak efficiency through decreasing the band broadening effect of mass transfer of analyte. Also, 2-(anilinomethyl) pyrrolidine was chromatographed at 0°C in order to optimize the selectivity of separation.

The GC equipment used was a Shimadzu (Columbia, MD) model GC-17A gas chromatograph equipped with a flame ionization detector and EZStart 7.2.1 SP1 data acquisition software. All analyses were performed with a helium carrier gas flow rate of 1 ml/min and a split ratio of 100/1. The injector and detector temperature was set at 250°C and 280°C, respectively. In all GC analyses, chiral compounds with amino and/or hydroxyl groups were derivatized with excess trifluoroacetic anhydride, an achiral reagent that does not induce any change of analyte configuration. 23

Typical enantiomeric separations on HPLC and GC are shown in Figure 3. All the results were calculated from at least 3 parallel measurements of sample with different concentrations. Each pair of enantiomers were separated with resolution greater than 1.5, so that when an excessive amount of a single enantiomer was injected, its broadening baseline width would not cause a co-elution of the single enantiomer being tested and the enantiomeric impurity.

Figure 3.

Figure 3

Chromatograms A show the enantiomeric separation of 1-indanol on HPLC and the impurity tested in the (R)-enantiomer purchased from Aldrich. Chromatograms B show the enantiomeric separation of 4-(chloromethyl)-2, 2-dimethyl-1, 3-dioxolane on GC and the assay of the (S)-enantiomer obtained from Aldrich. The separation methods for A and B are listed in Table 3 as LC-7 and GC-11, respectively.

Acknowledgments

Support of this work by the National Institute of Health (GM053825-11) is gratefully acknowledged.

Footnotes

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