2
V. Mikhailenko et al. / Tetrahedron Letters xxx (2015) xxx–xxx
Diastereomeric ratios (dr) determined for derivates 6a–f
H3CO
F3C
O
CH3
CF3
COOH
OH
O
(around 50:50) showed good compliance to the equal amount of
enantiomers expected in the starting racemic alcohols rac-5a–f
(Table 1, entries 1–3 and 5–7). However, in the case of rac-6g–i
(Table 1, entries 8–10), the dr value could not be accurately deter-
mined due to low separation of the corresponding chromato-
graphic peaks.
In order to compare our results to the known derivatizing agent
MTPA (1),7,8 we performed the derivatization of rac-5c with (R)-
MTPA under the same reaction conditions16 followed by GC analy-
sis of the mixture of diastereomeric esters (R)-7c and (S)-7c
(Scheme 2). The only difference was that centrifugation was used
instead of filtration in order to exclude possible errors arising from
different retention of the diastereomeric esters on silica. As shown
in Table 1, use of (R)-MTPA (1) provided considerably higher reso-
O
Cl
OH
H3C
O
HO
O
O
O
2
3
1
4
Figure 1. Structures of selected chiral derivatizing agents 1–4 for determining the
enantiomeric purity of chiral secondary alcohols.
acted 4 and N,N0-dicyclohexylurea. The mixtures were analyzed by
GC and HPLC (see ESI for details).
The (R)- or (S)-configurations in the mixtures of diastereomeric
esters 6a–6d and 7c (see Scheme 2 and the discussion thereof)
were assigned by comparison to their enantiomerically pure deri-
vates, (R)-6 and (S)-6, synthesized from the corresponding enan-
tiomerically pure alcohols (R)-5a–d and (S)-5a–c, respectively
(details regarding the synthesis and characterization of these stan-
dards, (R)-6 and (S)-6, are given in ESI). Esters (R)-6 and (S)-6
showed equal absorbance at the wavelength (kmax) 245 nm which
was chosen as the analytical wavelength for HPLC analyses. The
results of HPLC and GC analyses of derivates 6a–i are given in
Table 1.
As can be seen from Table 1, using HPLC, the series of diastere-
omeric esters 6a–d formed from the homologous 1,1,1-trifluoro-2-
alkanols rac-5a–d (Table 1, entries 1–3 and 5) showed that resolu-
tion (RS) increased with longer alkyl chain lengths. However, even
in the case of the lowest RS values (entry 1), it was high enough to
separate the analytes almost to baseline, which allowed reliable
determination of minor components at a level of less than 1%. Thus,
such RS values were considered to be sufficient for further applica-
tions. The effect of the alkyl chain was less pronounced in GC sep-
arations where modest resolution values were obtained. Moreover,
RS values reached a maximum for ester 6c containing an interme-
diate terminal alkyl length (entry 3). Diastereomeric esters 6e,f
derived from aryl-substituted trifluoromethyl alkanols 5e,f showed
excellent separation using HPLC and modest to good separation
when GC was employed (entries 6 and 7). In the case of compounds
6e,f, the resolution was substantially increased when the benzene
ring was substituted with a methyl group (compare entries 6 and
7). In comparison to the fluorine-containing compounds 5a–f
lution of the analytes under GC conditions than L-menthyl phtha-
late (4) (compare entries 3 and 4). Due to such high resolution,
the diastereomeric esters (R)-7c and (S)-7c were fully separated
by GC–MS and their individual mass-spectra confirmed the
expected structures. However, in this case, the diastereomeric ratio
(R)-7c/(S)-7c surprisingly indicated a prevalence for one of the
diastereomers.
In order to assign the chromatographic peaks, 10% by weight of
enantiomerically pure alcohol (S)-5c was added to (R)-5c (esti-
mated ee 100%). Derivatization of this mixture with (R)-MTPA (1)
gave a mixture of diastereomers (R)-7c and (S)-7c where 6.3% of
(S)-7c was detected by GC. At the same time, using L-menthyl
phthalate (4) for derivatization of the same mixture, gave diastere-
omers (R)-6c and (S)-6c with the expected ratio (10.3% by HPLC,
10.2% by GC). These results indicate that using (R)-MTPA (1) leads
to an overestimation of the amount of the corresponding (R)-alco-
hol in a mixture of enantiomers. Thus, L-menthyl phthalate (4) is
well suited as a derivatizing agent for the determination of enan-
tiopurity for alkyl- and aryl-substituted trifluoromethyl alkanols
under both HPLC and GC conditions. At the same time, the applica-
bility of 4 for analysis of the enantiomeric purity for non-fluori-
nated alcohols 5g–i should be considered as limited.
For the purpose of obtaining homologous (R)-enantiomeric
1,1,1-trifluoromethyl-2-alkanols (R)-5a–d, racemic alkanols rac-
5a–d were first synthesized from ethyl trifluoroacetate by means
of a Grignard addition/reduction sequence17 followed by conver-
sion to the corresponding chloroacetates rac-8 (Scheme 3).
Lipase-catalyzed enzymatic hydrolysis8 proceeding with a conver-
sion of less than 50% (according to GC–MS) gave a mixture of (R)-
enantiomeric alcohol (R)-5, residual ester (R)-8, and unreacted
ester (S)-8. The mixture could be separated by fractional distilla-
tion under reduced pressure to give alcohol and ester containing
fractions.
(Table 1, entries 1–3 and 5–7), L-menthyl phthalate (4) appeared
to be a considerably less effective derivatizing agent for non-fluo-
rinated alcohols rac-5g–i. In these cases, satisfactory separation
was only achieved using HPLC for ( )-2-octanol derivatives 6g
(entry 8) while the derivatives of rac-menthol (6h) (entry 9) and
1-phenyl-2-propanol (6i) (entry 10) showed no noticeable separa-
tion. A similar tendency was also observed for the GC analyses of
diastereomers 6g–i (entries 8–10).
R1
R1 R2
R1 R2
O
O
O
OH
HO
R2
O
O
O
O
O
i
+
+
+
O
O
O
R1
HO
R2
4
5a-i
rac-
(R)-6a-i, (S)-6a-i
1
2
1
2
5a
5f
R =CF3, R =p-(C6H4)-CH3
R =CF3, R =C4H9
5b R1=CF3, R2=C5H11 5g
5c R1=CF3, R2=C6H13
1
2
R =CH3, R =C6H13
5d R1=CF3, R2=C7H15 5h R1,R2=
5e R1=CF3, R2=Ph
5i R1=CH3, R2=CH2Ph
Scheme 1. Derivatization of racemic secondary alcohols (rac-5a–i) with
L-menthyl phthalate (4). Reagents and conditions: (i) DCC, DMAP, 1,2-dichloroethane, 0 °C–rt.