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

Article abstract of DOI:10.1016/j.tetasy.2006.10.014

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 impurity levels (i.e., <0.01%, 0.01-0.1%, 0.1-1%, 1-10%, 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.

Full text of DOI:10.1016/j.tetasy.2006.10.014

Tetrahedron: Asymmetry 17 (2006) 2821–2832
Enantiomeric impurities in chiral synthons, catalysts, and
auxiliaries: Part 3
Ke Huang, Zachary S. Breitbach and Daniel W. Armstrong*
Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX 76019, USA
Received 29 September 2006; accepted 9 October 2006
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 compo-
sition. These compounds are widely used in asymmetric syntheses as chiral synthons, catalysts, and auxiliaries. These include chiral alco-
hols, amines, amino alcohols, amides, carboxylic acids, epoxides, esters, ketones, and oxolanes among other classes of compounds. All
enantiomeric test results were categorized within five impurity levels (i.e., <0.01%, 0.01–0.1%, 0.1–1%, 1–10%, 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.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
compounds are employed in asymmetric synthesis, espe-
cially in the pharmaceutical industry, the underestimated
contaminants will introduce various amounts of enantio-
meric impurities in the ‘single-enantiomer’ reaction and
products. In biological processes, these undesired enantio-
meric byproducts usually show different effects and/or dif-
ferent pharmacokinetics/pharmacodynamics and thus have
different therapeutic values.3 Although the stereoselectivity
of asymmetric synthetic processes continues to improve, an
awareness of the enantiomeric composition of chiral re-
agents being used remains essential.
Enantioselective reactions are of great importance to chem-
ists involved in asymmetric synthesis. The enantiomeric
purity of a product is affected by three 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.
2. Results and discussion
Of the 84 chiral compounds tested, 85% of them were sep-
arated 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 triflu-
oroacetylated chiral stationary phase of the GTA column.4
Also, the GTA chiral stationary phase showed impressive
separating capabilities for ketones, epoxides, and halo-
genated acids. Examples of these include the separations
of 3-methylcyclopentanone, epoxybutane, and chloroprop-
ionic acid, respectively.
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 previ-
ously and/or have been introduced after 1999, when the
last comprehensive evaluation of commercial chiral com-
pounds was reported.2 When enantiomerically impure
*
Corresponding author. Tel.: +1 817 272 0632; fax: +1 817 272 0619;
e-mail: sec4dwa@uta.edu
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.10.014

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K. Huang et al. / Tetrahedron: Asymmetry 17 (2006) 2821–2832
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 prop-
erties in the GC enantiomeric separations of derivatized
(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
(Fig. 1) shows that the analysis time for the derivative is
shorter and the peaks are sharper (which makes the detec-
tion and quantitation of enantiomeric impurities much eas-
ier). Furthermore, the reversal of the elution order of the
two enantiomers prior to, and after, derivatization indi-
cates that the introduction of the trifluoroacetyl group
alters the separation mechanism. It has also been reported
that acetic anhydride, chloroacetic anhydride, dichloroace-
tic anhydride, and trichloroacetic anhydride may be used
for this same purpose.5
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–
1999. In both studies, 2% of the chiral compounds tested
contained enantiomeric impurities greater than 10%. How-
ever, the greatest enantiomeric impurity for any chiral
compound was found in the 1998 analysis of (R)-tert-but-
yl-4-formyl-2,2-dimethyl-3-oxazolidine, which was deter-
mined to contain 15.11% of the (S)-enantiomer. This is
just slightly higher than the 13.80% maximum enantio-
meric 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
1998–1999. However, there were higher percentages 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 enantio-
meric 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
Table 3 lists all chiral compounds examined in this study,
as well as references describing their use in asymmetric syn-
theses. The separation conditions for each compound as-
sayed are listed in Tables 1 and 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% and 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 enantio-
meric contaminants over 10%.
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 re-
agents. Since novel chiral compounds are constantly being
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.

K. Huang et al. / Tetrahedron: Asymmetry 17 (2006) 2821–2832
Table 1. Enantioselective methods by gas chromatography (GC)
2823
GC method numbera
Columnb
Length (m)
Temperature (ꢁC)
Flow rate (ml/min)
GC-1
GC-2
GC-3
GC-4
GC-5
GC-6
GC-7
GC-8
Chiraldex G-PN
Chiraldex G-TA
Chiraldex G-PN
Chiraldex G-TA
Chiraldex G-TA
Chiraldex G-TA
Chiraldex B-DM
Chiraldex G-TA
Chiraldex B-DM
Chiraldex G-BP
Chiraldex B-DM
Chiraldex B-DM
Chiraldex G-TA
Chiraldex G-TA
Chiraldex G-TA
Chiraldex G-TA
Chiraldex G-TA
Chiraldex G-TA
Chiraldex B-DM
Chiraldex G-TA
Chiraldex B-TA
Chiraldex G-BP
Chiraldex G-TA
Chiraldex B-DM
Chiraldex G-TA
20
30
20
30
30
30
20
30
20
20
20
20
30
30
30
30
30
30
20
30
20
20
30
20
30
110
110
100
115
100
130
130
95
150
135
90
140
60
140
120
65
50
160
80
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
GC-9
GC-10
GC-11
GC-12
GC-13
GC-14
GC-15
GC-16
GC-17
GC-18
GC-19
GC-20
GC-21
GC-22
GC-23
GC-24
GC-25
150
100
140
35
125
80
a This information is used to identify the separation techniques mentioned 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 Trade names for the GC columns used. Further information on these columns can be found in the Experimental section.
Table 2. Enantioselective methods by liquid chromatography (LC)
HPLC method numbera
Columnb
Mobile phasec (%, v/v)
Flow rate (ml/min)
LC-1
LC-2
LC-3
LC-4
LC-5
LC-6
LC-7
Chirobiotic T2
Chirobiotic T2
Poly-DPEDA
Cyclobond I 2000 AC
Cyclobond I 2000 AC
Cyclobond I 2000 AC
Cyclobond I 2000 DM
H2O:TEAA = 100:0.1, pH 4.1
ACN:HOAc:TEA = 100:0.15:0.15
Heptane:IPA:TFA = 95:5:0.1
H2O:TEAA = 100:0.1, pH 4.1
H2O:TEAA = 100:0.1, pH 4.1
0.25
1
0.25
1
1
0.25
1
H2O:TEAA = 100:0.3, pH 4.1 (0 ꢁC)
H2O:TEAA:CH3OH = 97:0.1:3, pH = 7.1
a The notation is used to identify the separation techniques mentioned in Table 3.
b Trade names for the HPLC columns used. All the full names can be looked up in the Experimental section.
c Mobile phase: ACN = acetonenitrile; TEAA = triethylammonium acetate; HOAc = acetic acid.
developed and added to the repertoire of synthetic organic
chemists,6–21 some knowledge as to their enantiomeric
composition and the availability of facile methods for their
analysis will remain important.
anin), and Poly-DPEDA (poly-N,N0-[(1R,2R)-1,2-diphen-
yl-1,2-ethanediyl]bis-2-propenamide).22 GC analysis was
performed using Chiraldex B-DM (di-O-methyl-b-cyclo-
dextrin), Chiraldex G-PN (2,6-di-O-pentyl-3-propionyl-c-
cyclodextrin), Chiraldex G-BP (2,6-di-O-pentyl-3-butyryl-
c-cyclodextrin), Chiraldex G-TA (2,6-di-O-pentyl-3-trifluo-
roacetyl-c-cyclodextrin) columns and Chiraldex B-TA (2,6-
di-O-pentyl-3-trifluoroacetyl-b-cyclodextrin).
3. Experimental
3.1. Materials
Trifluoroacetic anhydride (99+%) was from Aldrich (Mil-
waukee, WI). Trifluoroacetic acid was obtained from Fish-
er 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.
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-b-cyclodextrin), Cyclobond I 2000
DM (dimethylated-b-cyclodextrin), Chirobiotic T2 (teicopl-

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K. Huang et al. / Tetrahedron: Asymmetry 17 (2006) 2821–2832
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 Enantiomeric
contaminant
excess (ee)a
Synthons or chiral building blocks
2-Aminoheptane
NH2
*99.83 (R)
99.31 (S)
GC-1
(1) Development and synthesis
of 2-o-methylcytidine24
(S) = 0.09
(R) = 0.35
(2) Synthesis of amide analogues
of the cannabinoid CB1
receptor antagonist25
2-Amino-1-hexanol
NH2
(1) Synthesis of hydroxy
perylenediimides26
(2) Preparation of 4,5-dialkyl
substituted 2-amino-3-thiazolidine
derivatives as nitric oxide
synthase inhibitors27,28
(S) = 0.07
(R) = 0.09
*99.87 (R)
99.82 (S)
GC-2
GC-3
OH
(1) Enantioselective acylation29
(2) Synthesis of a new class of
nitric oxide synthase inhibitor,
4,5-disubstituted-1,3-oxazolidin-
2-imine derivatives30
2-Amino-1-pentanol
(S) < 0.01
(R) < 0.01
*>99.99 (R)
>99.99 (S)
NH2
OH
2-Amino-1-phenyl-
1,3-propanediol
(1) Synthesis of crystalline chelates31
(2) Preparation of imidazo[1,2-b]pyridazines
under Swern oxidative conditions32
(S,S) = 0.52
(R,R) = 0.06
*98.97 (R,R)
>99.89 (S,S)
GC-4
GC-5
OH
HO
NH2
(S) = 0.28
(R) = 0.93
99.44 (R)
*98.14 (S)
3-Amino-1,2-propanediol
(1) Structure–activity relationship study of
1H-imidazo [4,5-c]quinolines that
induce interferon production33
(2) Preparation of 20-aldehyde
oligonucleotides for chemoselective
ligation study34
H2N
OH
OH
3-Aminopyrrolidine
Synthesis of antitumor agent35,36
(S) = 0.66
(R) = 0.17
98.67 (R)
*99.67 (S)
GC-5
GC-6
HN
NH2
1-Benzyl-3-aminopyrrolidine
N
Potential human dopamine D4
antagonists synthesis37
(S) = 0.17
(R) < 0.01
*99.67 (R)
>99.99 (S)
NH2
4-Benzyl-3-propionyl-
2-oxazolidinone
(1) Preparation of Evans auxiliary38,39
(2) Chemoenzymatic synthesis of the
polyketide macrolactone 10-deoxymethynolide40
(3) Asymmetric total synthesis of
(+)-migrastatin, a potent cell
(S) = 0.37
(R) < 0.01
99.26 (R)
*>99.99 (S)
GC-7
O
H3C
N
migration inhibitor41
O
O

K. Huang et al. / Tetrahedron: Asymmetry 17 (2006) 2821–2832
2825
Table 3 (continued)
Use in asymmetric synthesis and references
Name and structure
of chiral compound
Enantiomeric composition
Method
numberb
% Enantiomeric Enantiomeric
contaminant
excess (ee)a
*87.03 (R,R)
93.43 (S,S)
GC-8
Bis(α-methylbenzyl)sulfamide
Ring-closing metathesis to cyclic
sulfamide peptidomimetics42
(S,S) = 6.49
(R,R) = 3.29
O
S
NH
NH
O
2-Bromo-α-methylbenzyl-alcohol
(1) Starting material of chiral
diamine-chelated aryllithiums43
(S) = 0.36
(R) = 0.14
*99.29 (R)
99.73 (S)
GC-9
(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
OH
Br
*99.53 (R)
99.16 (S)
GC-10
1-(4-Bromophenyl)ethylamine
(S) = 0.24
(R) = 0.42
(1) Synthesis of 2,3-diminopyridine bradykinin
B1 receptor antagonists46
(2) Preparation of substituted N-(arylmethyl)aryloxy
arylcarboxamide antagonists for the PGE2 receptor
EP447
NH2
Br
*98.33 (R)
>99.99 (S)
GC-5
1,2,4-Butanetriol
OH
(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
(S) = 0.84
(R) < 0.01
OH
HO
4-(Chloromethyl)2,2-dimethyl-
1,3-dioxolane
Synthesis of 1,2-dihydroxyimino-3,7-di-aza-
9,10-O-iso-propylidene decane, a vic-dioxime
derivative for its metal complex study51
(S) = 0.12
(R) = 0.28
99.76 (R)
*99.45 (S)
GC-11
GC-12
O
Cl
O
(1) Used as substrates in transesterification
of vinyl esters52
(S) = 0.39
(R) = 0.24
*99.22 (R)
99.53 (S)
3-Chloro-1-phenyl-1-propanol
OH
(2) Lanthanide (III) triflate-catalyzed
thermal and microwave-assisted
Cl
synthesis of benzyl ethers53
(3) Synthesis of 3-phenoxypropyl piperidine
analogues as ORL1 receptor agonists54
(4) Preparation of fluoxetine analogues,
a novel class of anticandida agents55
(1) Synthesis and structure–activity
relationship study of ethacrynic acid
analogues on glutathione-s-
(S) = 2.79
(R) = 0.38
*94.42 (R)
99.25 (S)
GC-5
Chloropropionic acid
transferase P1-1 inhibition56
Cl
COOH
(2) Synthesis of a peroxime proliferator
activated receptor (PPAR) a/c agonist57
(continued on next page)

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K. Huang et al. / Tetrahedron: Asymmetry 17 (2006) 2821–2832
Table 3 (continued)
Use in asymmetric synthesis and references
Name and structure
of chiral compound
Enantiomeric composition
Method
numberb
% Enantiomeric Enantiomeric
contaminant
excess (ee)a
(S) = 0.29
(R) = 1.38
*99.42 (R)
97.25 (S)
GC-13
β-Citronellol
(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
OH
(5) Stereoselective synthesis of
Fusarium toxin equisetin, a potent HIV-1
integrase enzyme62
1-(2-Methoxybenzoyl)-
2-pyrrolidinemethanol
(S) < 0.01
(R) < 0.01
>99.99 (R)
>*99.99 (S)
LC-1
(1) Study of a new method to
oxidize primary alcohols
to carboxylic acids63
OH
O
O
(2) Study of the influence of the nature
of chiral auxiliaries on the diastereoselective
hydrogenation of o-methoxy benzoic acid64
(3) Used in the study of reductive
alkylation of aromatic carboxylic acid derivatives65
N
(1) Preparation of chiral crown ethers66–68
(2) Starting material for the synthesis of (3R,4S)-
3,4-dihydroxy-5-oxohexylphosphonic acid69
(3) Synthesis through Mitsunobu reaction
of chiral diesters and chiral diamines
(ꢀ) = 7.42
*85.16 (+)
99.60 (ꢀ)
GC-14
2,3-O-Benzylidene-D-threitol
(+) = 0.20
OH
HO
O
O
as macrocyclic frameworks70
Ethyl-4-bromo-
3-hydroxybutyrate
Synthesis of lower alkyl 4-cyano-3-hydroxybutyrates71
(S) = 0.37
(R) = 0.36
99.26 (R)
*99.29 (S)
GC-15
OH
O
Br
O
Ethyl-4-chloro-
3-hydroxybutyrate
(S) = 0.49
(R) = 0.04
*99.02 (R)
99.93 (S)
GC-15
GC-16
(1) Substrate for enzymatic ammonolysis72
(2) Synthesis of 4-cyano-3-hydroxybutyric acid esters73
(3) Preparation of epoxybutanoic acid esters74
OH
O
Cl
O
(S) = 0.12
(R) = 1.32
99.77 (R)
*97.36 (S)
2-Heptanol
(1) Alkanol absolute configuration study with
cyclopenta[b]furan derivative75
OH
(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-(4-Hydroxyphenoxy)
propionic acid
Synthesis of analogues of antitumor agents
for action mechanism study of XK469 and SH8080,81
(S) < 0.01
>99.99 (R)c
LC-2
O
O
HO

K. Huang et al. / Tetrahedron: Asymmetry 17 (2006) 2821–2832
2827
Table 3 (continued)
Use in asymmetric synthesis and references
Name and structure
of chiral compound
Enantiomeric composition
Method
numberb
% Enantiomeric Enantiomeric
contaminant
excess (ee)a
(S) < 0.01
(R) < 0.01
>99.99 (R)
>*99.99 (S)
LC-3
6-Hydroxy-2,5,7,8-tetramethyl-
chroman-2-carboxylic acid
(1) Starting material for the synthesis of a
new class of antiatherosclerosis agents,
the NO-donor antioxidants82
HO
(2) Building 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
O
OH
O
(S) = 0.10
99.80 (R)c
GC-17
3-Methylcyclopentanone
O
(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 1,6,6ak4-trithiapentalenes88
2-Methylpiperazine
(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
(S) = 0.13
(R) = 0.15
99.75 (R)
*99.71 (S)
GC-6
H
N
N
H
92
Synthesis of 10-azaprostaglandin E1
(S) < 0.01
(R) = 0.62
*>99.99 (R)
98.76 (S)
GC-18
5-Oxo-3-pyrrolidinecarboxylic
acid ethyl ester
O
HN
O
O
Efficient synthesis of cyclopentenones
from enynyl acetates93
(S) = 0.20
(R) = 0.17
99.61 (R)
*99.77 (S)
GC-19
GC-13
GC-20
GC-2
1-Octyn-3-ol
OH
(S) = 1.11
(R) = 0.39
*97.79 (R)
99.22 (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
OH
3-Pyrolidinol
(S) = 0.04
(R) = 0.54
*99.92 (R)
98.92 (S)
(1) Starting material for the synthesis of
1-arylmethyl-3-(1-methyl-2-amino)
OH
HN
ethyl-5-aryl-6-methyluracils, a new
class of small molecule GnRH antagonists96
(2) Preparation of tri- and tetra-substituted
ureas as a novel class of steroid mimics97
α-(Trifluoromethyl)benzyl
alcohol
Used in the study of enantioselective
palladium(II)-catalyzed aerobic alcohol
oxidations with (ꢀ)-sparteine98,99
(S) = 1.06
(R) = 1.32
*97.88 (R)
97.36 (S)
OH
CF3
(continued on next page)

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K. Huang et al. / Tetrahedron: Asymmetry 17 (2006) 2821–2832
Table 3 (continued)
Use in asymmetric synthesis and references
Name and structure
of chiral compound
Enantiomeric composition
Method
numberb
% Enantiomeric Enantiomeric
contaminant
excess (ee)a
Important synthetic component of
ferroelectric liquid crystals100
(S) = 0.90
(R) = 0.56
*98.20 (R)
98.88 (S)
GC-21
1,1,1-Trifluorooctan-2-ol
OH
F3C
Catalyst/catalyst ligands
Solid support catalysis for
hydrosilylation of ketones101
2-Amino-1,2-diphenylethanol
NH2
(1S,2R) < 0.01
(1R,2S) < 0.20
*>99.99 (1R,2S) GC-22
99.60 (1S,2R)
OH
Solid support catalysis for
hydrosilylation of ketones101
(S) = 0.23
(R) = 0.74
*99.54 (R)
98.52 (S)
GC-3
2-Amino-3-methyl-1-butanol
NH2
OH
*95.70 (R)
93.66 (S)
GC-20
2-Amino-1-phenylethanol
Solid support catalysis for
hydrosilylation of ketones101
(S) = 2.15
(R) = 3.17
OH
NH2
Bis (α-methylbenzyl)amine
(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
(S) < 0.01
(R) = 0.61
*>99.99 (R)
98.79 (S)
LC-4
N
H
Epoxybutane
O
(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
(S) = 0.13
(R) = 0.01
*99.74 (R)
99.98 (S)
GC-23
Accelerators for hydrosilation of
unsaturated organic compounds108
(S) = 2.02
(R) = 0.15
*95.96 (R)
99.70 (S)
GC-24
1-Phenyl-2-propyn-1-ol
OH
2-Amino-1,1-diphenyl-
1-propanol
Chiral auxiliaries
NH2
Asymmetric alkynylation of aromatic ketones109
(S) = 1.26
(R) < 0.01
*97.49 (R)
>99.99 (S)
LC-5
OH

K. Huang et al. / Tetrahedron: Asymmetry 17 (2006) 2821–2832
2829
Table 3 (continued)
Use in asymmetric synthesis and references
Name and structure
of chiral compound
Enantiomeric composition
Method
numberb
% Enantiomeric Enantiomeric
contaminant
excess (ee)a
(S) = 9.18
(R) = 4.98
*81.64 (R)
90.04 (S)
LC-6
2-(Anilinomethyl)pyrrolidine
(1) Synthesis of (S)-fontalin
and its antipode110
(2) Synthesis of malyngolide,
a marine antibiotic111
(3) Synthesis of sarcophytol A,
an anticarcinogenic marine cembranoid112
H
N
NH
2,5-Dihydro-3,6-dimethoxy-2-iso
propylpyrazine
Scholkopf chiral auxiliary113–117
(S) = 4.59
(R) = 2.37
90.83 (R)
*95.26 (S)
GC-11
GC-25
N
O
O
N
2,2-Dimethyl-1,3-dioxolane-
4-methanol
(S) = 2.23
(R) = 2.40
95.55 (R)
*95.21 (S)
(1) Synthesis of a-(1-methylethyl)-a-
(3-oxopropyl)benzeneacetonitriles118
(2) Chiral resolution of 6-phenyl-4-
phenylethynyl-1,4-dihydropyridines,
A3 adenosine receptor antagonists119
O
HO
O
1-Indanol
OH
NMR configuration assignment of
a-carboxylic acids120
(S) = 13.8
(R) = 11.1
*72.50 (R)
77.80 (S)
LC-7
Lactamide
OH
Dynamic kinetic resolution of
a bromoesters121
(S) = 1.10
(R) = 1.12
97.80 (R)
*97.77 (S)
GC-15
NH2
O
a
*
The first eluted peaks are indicated with the sign
.
b GC = gas chromatography, LC = liquid chromatography (here high performance liquid chromatography). Each method is taken from Tables 1 and 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.
50%
SCL-10A system controller; and a CR 601 Chromatopac
45%
40%
35%
30%
25%
20%
15%
10%
5%
1998-99
2006
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-meth-
oxybenzoyl)-2-pyrrolidinemethanol to increase peak effi-
ciency through decreasing the band broadening effect of
mass transfer of analyte. Also, 2-(anilinomethyl) pyrroli-
dine was chromatographed at 0 ꢁC in order to optimize
the selectivity of separation.
0%
<0.01
0.01 to 0.1 0.1 to 1
1 to 10
>10
% of enantiomeric impurity
Figure 2. Comparison of results obtained in this study (2006) and results
obtained in prior work (1998–1999).
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 and
280 ꢁC, respectively. In all GC analyses, chiral compounds
with amino and/or hydroxyl groups were derivatized with
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

2830
K. Huang et al. / Tetrahedron: Asymmetry 17 (2006) 2821–2832
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 2,2-dimethyl-1,3-dioxolane-4-methanol 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-25, respectively.
9. Tokuda, R.; Matsunaga, H.; Ishizuka, T.; Nakajima, M.;
Kunieda, T. Heterocycles 2005, 66, 135–141.
10. Hayashi, T. Shokubai 2005, 47, 533–538.
excess trifluoroacetic anhydride, an achiral reagent that
does not induce any change of analyte configuration.23
11. Sedlak, M.; Drabina, P.; Cisarova, I.; Ruzicka, A.;
Hanusek, J.; Machacek, V. Tetrahedron Lett. 2004, 45,
7723–7726.
12. Nesterrov, V. V.; Kolodiazhnyi, O. I. Tetrahedron: Asym-
metry 2006, 17, 1023–1026.
13. Enders, D.; Tedeschi, L.; Foerster, D. Synthesis 2006, 9,
1447–1460.
14. Wu, Y. T.; Hayama, T.; Baldridge, K. K.; Linden, A.;
Siegel, J. S. J. Am. Chem. Soc. 2006, 128, 6870–6884.
15. Mateus, N.; Routaboul, L.; Daran, J. C.; Manoury, E. J.
Organomet. Chem. 2006, 691, 2297–2310.
Typical enantiomeric separations on HPLC and GC are
shown in Figure 3. All the results were calculated from at
least three parallel measurements of sample with different
concentrations. Each pair of enantiomers was separated
with a resolution greater than 1.5, so that when an exces-
sive amount of a single enantiomer was injected, its broad-
ening baseline width would not cause a co-elution of the
single enantiomer being tested and the enantiomeric
impurity.
16. Lin, G.; Lu, W.; Chen, P. Faming Zhuanli Shenqin Gongkai
Shuomingshu 2006, 1743308.
17. Ichikawa, Y.; Matsukawa, Y.; Isobe, M. J. Am. Chem. Soc.
2006, 128, 3934–3938.
18. Penhoat, M.; Bohn, P.; Dupas, G.; Papamicael, C.; Marsais,
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19. Larrosa, I.; Romea, P.; Urpi, F. Org. Lett. 2006, 8, 527–530.
20. Du, Z. Y.; Xiao, R. T. Yingyong Huaxue 2005, 22, 1372–
1374.
Acknowledgment
Support of this work by the National Institute of Health
(GM053825-11) is gratefully acknowledged.
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