Enhanced chromatographic resolution of alcohol enantiomers as phosphate or phosphonate derivatives

Article abstract of DOI:10.1016/S0957-4166(01)00556-0

Phosphate and phosphonate derivatives of chiral alcohols show enhanced resolution by HPLC using a chiral support. Labile derivatives were also prepared that allow separation and recovery of the corresponding alcohol after basic hydrolysis.

Full text of DOI:10.1016/S0957-4166(01)00556-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 3063–3066
Enhanced chromatographic resolution of alcohol enantiomers as
phosphate or phosphonate derivatives
Yves Leblanc,a,* Claude Dufresne,a Rebekah Carson,a Louis Morencya and Christopher J. Welchb
aMerck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire–Dorval, Quebec, Canada H9R 4P8
bMerck & Co., Inc., 126 E. Lincoln Avenue, PO Box 2000, Rahway, NJ 07065-0900, USA
Received 1 October 2001; accepted 5 December 2001
Abstract—Phosphate and phosphonate derivatives of chiral alcohols show enhanced resolution by HPLC using a chiral support.
Labile derivatives were also prepared that allow separation and recovery of the corresponding alcohol after basic hydrolysis.
© 2002 Elsevier Science Ltd. All rights reserved.
O
1. Introduction
O
P(OEt)2
P(OEt)2
Cl
OH
R'
O
HPLC using a chiral support is a powerful analytical
method for measuring enantioenrichment.1 In cases
where sufficient resolution is obtained, chiral HPLC
may also be used for the isolation of useful quantities
of enantiopure materials.2 For poorly resolved mixtures
of enantiomers, conversion to more readily resolved
derivatives is often possible.3 While this approach has
lost some favor in recent years as the ability to separate
underivatized enantiomers has grown, derivatization
can still be a valuable tool for solving difficult or
challenging problems. Herein, we report the generally
improved resolution of some alcohol enantiomers as
their phosphate or phosphonate derivatives.
Py
R
R
R'
1
2
Scheme 1.
the cases studied, superior resolution was observed with
the phosphate derivative compared to the alcohol itself.
Benzylic phosphates showed remarkable baseline sepa-
ration as exemplified in Fig. 1 for compound 2a. Sepa-
ration was also observed in difficult cases such as
2-octanol 1h. The phosphate derivative 2h of 2-octanol
provided a resolution of 0.6. In the case of compounds
2f and 2g no resolution was achieved. For comparison
the pivaloyl derivatives4 were also prepared and sub-
jected to the same HPLC conditions. In all cases resolu-
tion was found to be lower than the corresponding
phosphates except in the cases of pivalates 10c and 10i.
2. Results and discussion
During the course of one of our projects it was
observed that chiral molecules containing a phospho-
nate moiety are well separated by HPLC on the Chiral-
pak® AD column. This observation suggested that
phosphate derivatives 2 (Scheme 1) of alcohols could
potentially be useful for evaluating the enantiopurity of
alcohols. Therefore, a series of phosphate analogs 2a–2i
of alcohols 1a–1i was prepared and then analyzed on a
Chiralpak AD analytical column using iso-propyl alco-
hol in hexane as the mobile phase (Table 1). In most of
To verify whether this unique separation was specific to
phosphate analogs or could also be extended to
molecules containing a phosphonate group, the ben-
zylphosphonate analogs of alcohols 1a, 1d and 1e were
also prepared. The (4-bromomethylbenzenephospho-
nate alkylating agent 5 was synthesized as described in
Scheme 2 from 4-iodotoluene 3.5 The derivatized alco-
hols 6a, 6d and 6e were then injected onto HPLC under
the previously described conditions. Very good resolu-
tion was obtained in the cases of 6d and 6e. Therefore,
even though the phosphonate group is remote from the
stereogenic center, it can still provide good separation.
* Corresponding author. Tel.: 1-514-428-3096; fax: 1-514-428-4900;
e-mail: yves leblanc@merck.com
–
0957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00556-0

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Y. Leblanc et al. / Tetrahedron: Asymmetry 12 (2001) 3063–3066
Table 1. Resolution parameters for racemic compounds on AD column with 10% iso-propanol/hexane12,13
column or to the technique of HPLC. We observed
These results led us to prepare labile derivatives of
alcohols containing a phosphonate group. The 4-phos-
phonate benzoic acid 8 was prepared as described in
Scheme 3.6 The alcohol was then treated with the acid
chloride in CH2Cl2 with pyridine in the presence of
DMAP. In all cases the observed resolution was supe-
rior than for the corresponding alcohols even with the
alcohols 1f and 1g where no separation was observed
with phosphate analogs.
improved resolution of the enantiomers of phosphate
and phosphonate derivatives using both HPLC and
supercritical fluid chromatography (SFC) on several
additional chiral supports including Chiralpak AS, Chi-
ralcel OJ and Whelko columns.
To be useful for preparative chromatography, a deriva-
tizing agent must be easily removed. Since the labile
phosphonate derivatives gave good resolution, we
decided to apply this method to the resolution of the
enantiomers of chiral alcohol, 1b, a precursor used in
Improved resolution of the enantiomers of phosphate
and phosphonate derivatives is not exclusive to the AD

Y. Leblanc et al. / Tetrahedron: Asymmetry 12 (2001) 3063–3066
3065
3. Conclusion
In summary, improved chromatographic resolution of
phosphate and phosphonate derivatives of chiral alco-
hols was demonstrated. The development of a labile
phosphonate derivatizing reagent allowed us to sepa-
rate appreciable quantities of enantiopure material and
to regenerate the corresponding alcohols after basic
hydrolysis. For now, the nature of the enhanced resolu-
tion of the enantiomers of phosphate and phosphonate
derivatives remains unclear.
Acknowledgements
Figure 1. HPLC Chromatogram of compound 2a on Chiral-
pak® AD column 10% iso-propanol/hexane.
The authors would like to thank Re´jean Fortin and
Jean-Franc¸ois Masson for technical assistance. Also,
thanks to Patrick Roy for useful suggestions in the
preparation of this article.
O
I
P(OEt)2
NBS / CCl4
Cu
+ P(OEt)3
References
3
4
1. (a) Taylor, D. R.; Maher, K. J. Chromatogr. Sci. 1992,
30, 67; (b) Okamoto, Y.; Kaida, Y. J. Chromatogr. Sci.
1994, 666, 403; (c) Oguni, K.; Oda, H.; Ichida, A. J.
Chromatogr. Sci. 1995, 694, 91; (d) Eliel, E. L.; Wilen, S.
H. Stereochemistry of Organic Compounds; Wiley: New
York, 1994.
O
O
P(OEt)2
P(OEt)2
1
NaH,THF
Br
O
R'
2. (a) McCoy, M. Chem. Eng. News 2000, 78, 17–19; (b)
Francotte, E. Chem. Anal. 1997, 142.
R
5
6
3. (a) Allenmark, S. Chromatographic Enantioseparation:
Methods and Applications, 2nd ed.; Ellis Horwood: New
York, 1991; (b) Pirkle, W. H.; Welch, C. J. J. Org. Chem.
1984, 49, 138; (c) Pirkle, W. H.; Welch, C. J. J. Liq.
Chromatogr. 1991, 14, 3387.
Scheme 2.
O
1) (COCl)2
CH2Cl2
DMF cat.
/
O
I
P(OEt)2
P(OEt)2
H
4. Hyun, M. H.; Koo, H. J.; Lee, G. S.; Han, S. C.
Pd(OAc)2, Ph3P
BnEt3NCl
CH3CN
Enantiomer 2000, 5, 499–503.
5. Williams, A.; Naylor, R. A.; Collyer, S. G. J. Chem. Soc.,
Perkin Trans 2 1973, 2, 25–33.
6. Kabachnik, M. M.; Solntseva, M. D.; Izmer, V. V.;
Novibora, Z. S.; Beletsbaya, I. P. Russ. J. Org. Chem.
1998, 34, 93–97.
2) 1, pyridine, DMAP
CH2Cl2
HO
O
HO
O
90º
7
8
O
P(OEt)2
7. The phosphate derivatives 2 were prepared as follows: to
a 4 M solution of the alcohol in pyridine, cooled at 0°C
was added diethyl phosphochloridate (1.3 equiv.). The
reaction mixture was allowed to warm to room tempera-
ture and stirred for 2 h. The reaction mixture was parti-
tioned between water and ether. The organic phase was
washed with 2N aqueous HCl and saturated aqueous
NaHCO3. The organic phase was dried over Na2SO4 and
evaporated to dryness. The residue was purified by flash
chromatography using as eluent hexane/ethyl acetate 1:1
to afford the desired phosphate derivative.
1) HPLC separation
2) NaOH, THF, MeOH
OH
R'
R
O
O
1
R
R'
9
Scheme 3.
the synthesis of one of our cyclooxygenase-2 inhibitors.
The benzoylphosphonate derivative 9b was prepared on
2 g scale in 60% yield. Preparative chromatography on
0.5 g scale afforded the individual enantiomers of 9b in
greater than 98% e.e. with excellent recovery.10 The
corresponding alcohols were regenerated in 83% yield
without loss of enantioenrichment by basic hydrolysis
with aqueous NaOH.11
8. The methylphenyl phosphonate derivatives 6 were pre-
pared as follows: to
a
solution of diethyl 4-
methylphenylphosphonate 45 (4.00 g, 17.4 mmol) in CCl4
(40 mL) was added NBS (3.10 g, 17.4 mmol) and a
catalytic amount of benzoyl peroxide. After photolysis
for a period of 2 h, the reaction mixture was diluted with
hexane (40 mL) and filtered over celite. Purification after
evaporation of the residue using flash chromatography

3066
Y. Leblanc et al. / Tetrahedron: Asymmetry 12 (2001) 3063–3066
with hexane/ethyl acetate 1:1 afforded 3.93 g (73%) of
compound 5. H NMR (500 MHz, acetone-d6) l 7.81 (m,
NMR (500 MHz, acetone-d6) l 8.29 (m, 2H), 8.01 (d,
2H), 7.96 (m, 2H), 7.81 (d, 2H), 6.59 (s, 1H), 5.34 (s, 1H),
5.14 (s, 1H), 4.14 (m, 4H), 3.15 (s, 3H), 1.79 (s, 3H), 1.31
(t, 6H). 13C NMR (125.6 MHz, acetone-d6) l 164.40,
144.83, 143.01, 141.58, 135.90, 134.47, 133.49, 132.33,
129.85, 128.00, 114.17, 78.98, 62.34, 43.78, 18.17, 16.18.
HRMS calcd for C22H28O7PS (M+H)+: 467.1293, found:
467.1295.
1
2H), 7.78 (m, 2H), 4.73 (s, 3H), 4.10 (m, 4H), 1.29 (t,
6H). 13C NMR (125.6 MHz, acetone-d6) l 143.05, 132.39,
129.72, 129.72, 62.06, 32.70, 16.15 HRMS calcd for
C11H17BrO3P (M+H)+: 307.0099, found: 307.0097.
To a solution of the alcohol in THF and cooled at 0°C
was added NaH. The mixture was stirred for 15 minutes.
Then diethyl [4-(bromomethyl)phenyl]phosphonate 5 (1.5
equiv.) was added and the solution was allowed to warm
to room temperature and stirred for 1 h. The reaction
was poured in water and extracted with ethyl acetate. The
organic phase was dried and evaporated to dryness. The
residue was purified by flash chromatography using hex-
ane/ethyl acetate (30:70) to afford desired methyl phenyl
phosphonate 6.
11. The resolved benzoate derivatives 9b (0.10 g,) were dis-
solved in THF/CH3OH (2:1, 2 mL) and treated with 2
equiv. of NaOH at room temperature for 1 h. The
mixtures were acidified with HCl 1N and extracted with
ethyl acetate. The extracts were dried over Na2SO4 and
evaporated to dryness. The residue was purified by flash
chromatography using as eluent hexane/ethyl acetate 30%
to afford both of the desired alcohols 0.040 g or 83%.
The optical rotation for alcohols 1b are −39.6 (c 0.5
acetone) and +41.9 (c 0.5, acetone) from more mobile and
less mobile esters, respectively. Data for alcohol from
more mobile esters: 1H NMR (500 MHz, acetone-d6) l
7.92 (2H, d), 7.68 (2H, d), 5.31 (1H, d), 5.22 (1H, s), 4.92
(1H, s), 4.81 (1H, d), 3.12 (3H, s), 1.59 (s, 3H). 13C NMR
(125.6 MHz, acetone-d6) l 149.87, 147.62, 140.43, 127.45,
127.42, 111.72, 76.79, 43.89, 17.17. HRMS calcd for
C11H15BrO3S (M+H)+: 227.0741, found: 227.0741.
9. The ester analogs 9 were prepared as follows: to a
solution of 4-(diethoxyphosphoryl)benzoic acid 86 in
CH2Cl2 cooled at 0°C was added a catalytic amount of
DMF followed by oxalyl chloride 1.2 equiv. The reaction
mixture was allowed to warm to room temperature and
stirred for 0.5 h. The reaction was then cooled to 0°C and
pyridine (2 equiv.) followed by the alcohol were added.
The reaction mixture was allowed to warm to room
temperature and stirred overnight. The reaction was
quenched with water and extracted with ethyl acetate.
The organic phase was washed with 2N aqueous HCl
solution twice and then with saturated aqueous NaHCO3.
The organic extracts were dried and evaporated to dry-
ness. The residue was purified by flash chromatography
with hexane/ethyl acetate (20:80) to afford the desired
benzoate derivative 9.
12. (a) Column: 0.46×25 cm; (b) K% : (Capacity factor of more
1
mobile enantiomer)=(retention time of more mobile
enantiomer−dead time/dead time; (c) a (separation fac-
tor)=(capacity factor of less mobile enantiomer/K% ; (d)
1
Rs (resolution factor)=2×(difference of retention times of
less and more mobile enantiomers/sum of the band width
of the two enantiomer peaks).
10. The 9b enantiomers were separated on a Chiralpak®
column (5×50 cm) using 40% EtOH in hexane to 80%
EtOH in hexane with a flow rate of 60 mL/min; u 270
nM; more mobile enantiomer [h]D +45.0 (c 0.86, acetone);
less mobile enantiomer [h]D −44.2 (c 0.6, acetone). 1H
13. All new compounds have been fully characterized spec-
troscopically and elemental composition established by
high-resolution mass spectroscopy or combustion analy-
sis.