Deracemization of 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH): Practical synthesis of (-)-(S)-HPPH

Article abstract of DOI:10.1016/j.tetasy.2004.07.007

In the presence of 10% NaOH in boiling MeOH enantiomerically enriched HPPH is racemized. This permits the deracemization of HPPH in the presence of brucine, giving enantiomerically pure (-)-(S)-HPPH [(-)-(S)-5-(4-hydroxyphenyl)- 5-phenylhydandoin].

Full text of DOI:10.1016/j.tetasy.2004.07.007

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2657–2660
Deracemization of 5-(4-hydroxyphenyl)-5-phenylhydantoin
(HPPH): practical synthesis of (ꢀ)-(S)-HPPH
Jens Riedner and Pierre Vogel*
`
´
Laboratoire de glycochimie et de synthese asymetrique, Swiss Federal Institute of Technology (EPFL), BCH,
CH-1015 Lausanne-Dorigny, Switzerland
Received 22 June 2004; accepted 5 July 2004
Available online 13 August 2004
Abstract—In the presence of 10% NaOH in boiling MeOH enantiomerically enriched HPPH is racemized. This permits the derace-
mization of HPPH in the presence of brucine, giving enantiomerically pure (ꢀ)-(S)-HPPH [(ꢀ)-(S)-5-(4-hydroxyphenyl)-5-phenyl-
hydandoin].
Ó 2004 Elsevier Ltd. All rights reserved.
1.Introduction
in the liver by microsomal enzymes and the major
metabolites are (S)-5-(4-hydroxyphenyl)-5-phenyl-
Phenytoin 1 (5,5-diphenylhydantoin, PHT) is a well-
known anticonvulsant employed for the treatment of
epileptic seizures and was first introduced as an antiepi-
leptic drug in 1938.1 It still remains a drug of first choice
for epilepsy, especially for grand mal, temporal lobe,
and psychomotor seizures.2 It has been demonstrated
(Scheme 1) that phenytoin is extensively metabolized
hydantoin (ꢀ)-2 or (S)-HPPH (70–80%) and (R)-5-(4-
hydroxyphenyl)-5-phenylhydantoin (+)-2 or (R)-HPPH
(5–8%).3 It has been shown that ( )-HPPH ( )-2 does
not possess any anticonvulsant properties. However,
there is currently a growing interest in studying the
pharmacological properties of both (+)-(R)-HPPH and
(ꢀ)-(S)-HPPH. Comparing the (+)-(R)-HPPH (+)-2
HO
HN
O
O
N
H
5-8%
Metabolism
liver
(+)-2 (+)-(R)-HPPH
HN
O
O
70-80%
N
H
1 (DPH)
OH
HN
O
O
N
H
(-)-2 (-)-(S)-HPPH
Scheme 1.
*
Corresponding author. Tel.: +41-21-693-93-71; fax: +41-21-693-93-55; e-mail: pierre.vogel@epfl.ch
Address: Schwarz Pharma Ltd., Shannon Free Zone, Shannon, Co. Clare, Ireland.
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.07.007

2658
J. Riedner, P. Vogel / Tetrahedron: Asymmetry 15 (2004)2657–2660
levels in patients treated with PHT, it has been shown
that in patients presenting gingival hyperplasia (GH)
(+)-(R)-HPPH levels were much higher than in patients
not presenting these symptoms.4 In the light of this, it is
believed that (+)-(R)-HPPH (+)-2 could play a vital role
in PHT induced wound healing.5 In the case of the (S)-
enantiomer (ꢀ)-2, there is a growing interest to under-
stand its potential role in the treatment of neuropathic
pain.
uses only catalytical amounts of KCN. We modified
the last route by using a NaOCl/TEMPO oxidation of
acyloin ( )-4 and a two-phase system consisting of n-
BuOH/KOH and PEG600 as phase transfer catalyst,
as suggested by Poupaert et al.,12 for the conversion of
diketone 5 into the methyl ether ( )-6.
Deracemization of compounds containing one stereo-
genic center requires a reversible epimerization process
that can be coupled with an irreversible enantioselective
reaction (dynamic kinetic resolution).13 Most common
procedures use enantioselective protonation of eno-
lates14 or carbanions,15 oxidation/reduction sequence
for secondary alcohols and amines16 or allylic rearrange-
ments.17 Deracemization of systems withquaternary
carbon centers is less common.18 As the latter systems
cannot be deprotonated or oxidized to generate prochi-
ral sp2-C intermediates, heterolyses must be applied to
equilibrate them with either a carbenium or a carbanion
ion intermediate or withan alkenyl system throughan
elimination. We have found that the latter process can
be applied for the deracemization of ( )-2. We observed
that enantiomerically enriched (+)-2 or (ꢀ)-2 were race-
mized under basic conditions (0.5N NaOH) at room
temperature most probably following the mechanism
shown in Scheme 3.
In 1975, Claesen et al.6 resolved ( )-2 in low yield (9%)
by fractional crystallization of the diastereomeric
brucine salts and established their absolute configura-
tion by X-ray single-crystal diffraction of the (+)-10-
camphorsulfonate of (+)-2. Several chromatographic
methods have been reported for the resolution of (+)-2
and (ꢀ)-2.7 More recently super/subcritical fluid chro-
matography separations has been claimed to be amena-
ble to preparative resolution of ( )-2.8,9 We report
herein an unprecedented deracemization of ( )-2, wh ich
allows one to prepare (ꢀ)-2 in large amounts, readily.
2.Results and discussion
Racemic HPPH ( )-2 can be obtained in one step (44%
yield from 4-hydroxybenzophenone and NH4CO3,
EtOH, KCN, 120°C, 18h) through a modified Bucherer
–Lieb10 synthesis, or according to the Biltz route11
(Scheme 2), which is better suited for large-scale produc-
tion because it does not require pressurized vessels and
In the presence of an excess of NaOH, (+)-2 generates
phenolate (R)-7 that undergoes C–N heterolysis (E1cb-
like elimination) giving intermediate 8, which equili-
brates by intramolecular nucleophilic addition with
O
O
O
PhCHO
NaOCl, KBr
TEMPO
CH2Cl2/H2O
-10°C (90%)
Ph
OH
Ph
H
Et3N, KCN
EtOH, ∆
(72%)
O
MeO
MeO
OR
MeO
5
3
4
H
N
Ph
Ref. 12
urea, KOH
(93%)
1. brucine, MeOH, NaOH
2. 1 N HCl
O
(-)-2 (59%) e.e. >99.5%
N
O
H
AlCl3, EtSH
0-20°C (100%)
( )-6 R = Me
( )-2 R = H
Scheme 2.
O
Na
O
O
Na
H
N
H
N
Ph
Ph
Ph
O
NaOH
NaOH
HN
O
O
N
H
(R)-7
N
H
(S)-7
O
O
N
H
Na
O
8
NaOH
( )-(+)-2
Scheme 3. Racemization of HPPH.

J. Riedner, P. Vogel / Tetrahedron: Asymmetry 15 (2004)2657–2660
2659
(R)-7 and (S)-7. In the presence of a catalytic amount
Acknowledgements
(10%) of NaOH in MeOH, racemization of (+)-2 is slow
at room temperature, but fast in boiling MeOH. This
has allowed one to find a procedure in which the bru-
cine-(ꢀ)-2 complex precipitates from a boiling MeOH
solution of ( )-2. After decomplexation with1N HCl
(solid/H2O–HCl extraction), pure (ꢀ)-2 was obtained
in 59% yield and ee >99.5% (by chiral HPLC7j).
We thank the Swiss National Science Foundation for
support and Mr. A. Bouaziz for discussions. We are
grateful also to Mr. M. Rey and F. Sepu´lveda for tech-
nical help.
References
1. Merritt, H.; Puttman, T. JAMA 1938, 111, 1068–1073.
2. Penry, J.; Newmark, M. Ann. Int. Med. 1979, 89, 207–218;
Perruca, E. Br. J. Clin. Pharmacol. 1996, 42, 531–543;
Hadjipavlou-Litina, D. Med. Res. Rev. 1998, 18, 91–119;
Sutherland, J. J.; Weaver, D. F. J. Chem. Inf. Comput. Sci.
2003, 43, 1028–1036.
3. Butler, J. Pharmacol. Exp. Ther. 1957, 119, 1–11; Maguire,
J. H.; McClanahan, J. S. Adv. Exp. Med. Biol. 1986, 197,
897–902; Fritz, S.; Lindner, W.; Roots, I.; Frey, B. M.;
Kuepfer, A. J. Pharmacol. Exp. Ther. 1987, 241, 615–622;
Vree, T. B.; Steegers-Theunissen, R. P. M.; Baars, A. M.;
Hekster, Y. A. J. Chromatogr. 1990, 526, 581–589; Ieri, I.;
Mamiya, K.; Urae, A.; Wada, Y.; Kimura, M.; Irie, S.;
Amamoto, T.; Kuboda, T.; Yoshioka, S. Br. J. Clin.
Pharmacol. 1997, 43, 441–445.
3.Conclusion
A very simple procedure has been found to deracemize
( )-5-(4-hydroxyphenyl)-5-phenylhydantoin ( )-2 into
(ꢀ)-(S)-2 withgood yield and highenantiomeric purity.
Using other homochiral bases than brucine (+)-(R)-2
might be obtained in a similar way. The deracemization
of ( )-2 relies probably on a C–N heterolytical process
that is analgous to a E1cb-elimination, withgeneration
of a para-quinomethane intermediate.
4.Experimental
General, see Ref. 19.
4. Ieiri, I.; Goto, W.; Hirata, K.; Toshitani, A.; Imayama, S.;
Ohyama, Y.; Ohtsubo, K.; Higuchi, S. Eur. J. Clin.
Pharmacol. 1995, 49, 51–56.
5. Talas, G.; Brown, R. A.; McGrouther, D. A. Biochem.
Pharmacol. 1999, 57, 1085–1094.
4.1. ( )-5-(4-Hydroxyphenyl)-5-phenylhydantoin (+)-2
6. Poupaert, J. H.; Cavalier, R.; Claesen, M. H.; Dumont,
P. A. J. Med. Chem. 1975, 18, 1268–1271.
Method A: To a solution of ( )-620 (15.0g, 53mmol) in
EtSH (105mL) was added at 0°C AlCl3 (21.2g,
159mmol). The reaction was stirred at room tempera-
ture for 2h. Ice water was added and the precipitated
compound was isolated by filtration (14.2g, 100%).
Mp 306°C decomp. (lit.20 220–221°C). 1H NMR
(400MHz, DMSO-d6) d 6.77 (d, 2H, 3J = 8.9Hz,
ArH), 7.13 (d, 2H, 3J = 8.9Hz, ArH), 7.34–7.40 (m,
5H, Ph), 9.19 (s, 1H, NH), 9.61 (br s, 1H, PhOH),
11.02 (br s, 1H, NH). 13C NMR (100MHz, DMSO-d6)
75.1, 120.3, 131.8, 133.1, 133.6, 135.5, 145.4, 161.2,
162.3, 180.5.
7. (a) McClanahan, J. S.; Maguire, J. H. J. Chromatogr.
Biomed. Appl. 1986, 381, 438–446; (b) Fritz, S.; Lindner,
W.; Roots, I.; Frey, B. M.; Kuffer, A. J. Pharmacol. Exp.
Ther. 1987, 241, 615–622; (c) Vree, T. B.; Steegers-
Theunissen, R. P. M.; Baars, A. M.; Hekstger, Y. A. J.
Chromatrogr. 1990, 526, 581–589; (d) Eto, S.; Noda, H.;
Noda, A. J. Chromatogr. B 1991, 568, 157–163; (e) Hsieh,
C. Y.; Huang, J. D. J. Chromatogr. Biomed. Appl. 1992,
575, 109–115; (f) Pirkle, W. H.; Gan, K. Z. J. Chromatogr.
A
1997, 790, 65–71; (g) Ekborg-Ott, K.; Liu, Y.;
Armstrong, D. W. Chirality 1998, 10, 434–483; (h)
Karlsson, C.; Wikstrom, H.; Armstrong, D. W.; Owens,
P. K. J. Chromatogr. A 2000, 897, 349–363; (i) Agnew-
Heard, K. A.; Shamsi, S. A.; Warner, I. M. J. Liq.
Chromatogr. Rel. Technol. 2000, 23, 1301–1317; (j) Yao, T.
W.; Zeng, S. Biomed. Chromatogr. 2001, 15, 141–144.
8. Liu, Y.; Berthod, A.; Mitchel, C. R.; Xiao, T. L.; Zhang,
B.; Armstrong, D. W. J. Chromatogr. A 2002, 978,
185–204.
9. Lavison, G.; Thiebault, D. Chirality 2003, 15, 630–636.
10. Bucherer, H. T.; Lieb, V. A. J. Prakt. Chem. 1934, 141, 5.
11. Biltz, H.; Slotta, K. J. Prakt. Chem. 1926, 113, 232–267.
12. Poupaert, J. H.; De Keyser, J. L.; Vandervorst, D.;
Dumont, P. Bull. Soc. Chim. Belg. 1984, 93, 493–495.
13. Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Soc. Chim.
Jpn. 1995, 68, 36–56; Ward, R. S. Tetrahedron: Asymmetry
1995, 6, 1475–1490; El Gihami, M. T.; Williams, J. M. J.
Curr. Opin. Chem. Biol. 1999, 10, 4079–4081; Huerta, F.
F.; Minidis, A. B. E.; Baeckvall, J.-E. Chem. Soc. Rev.
2001, 30, 321–331; Pellissier, H. Tetrahedron 2003, 59,
8291–8327; Andraos, J. J. Phys. Chem. A 2003, 107,
2374–2387.
Method B: A high pressure reactor was charged with 4-
hydroxybenzophenone (8.00g, 40mmol), KCN (3.2g,
49mmol), ammonium carbonate (11.6g, 121mmol),
EtOH (30mL), and H2O (30mL). The reactor was
sealed and heated to 120°C for 18h. H2O (150mL)
was added and the mixture was boiled without reflux
for 20min, cooled, and filtered. The solids were recrys-
tallized from EtOH yielding white crystals (4.8g, 44%)
withidentical physical and spectroscopical properties
as above.
4.2. (ꢀ)-(S)-5-(4-Hydroxyphenyl)-5-phenylhydantoin (ꢀ)-
2
Brucine (4.41g, 11.2mmol) ( )-2 (3.00g, 11.2mmol) and
NaOH (45mg, 1.2mmol) were dissolved in the minimum
amount of boiling MeOH. The resulting hydantoin–bru-
cine complex crystallized slowly. It was decomplexed by
14. See for example: Duhamel, L.; Plaquevent, J.-C. Tetra-
hedron Lett. 1977, 26, 2285–2288; Gerlach, U.; Hunig, S.
solid liquid extraction with1N HCl giving ( ꢀ)-2 (1.77g,
¨
25
59%). ½aŠ ¼ ꢀ22:4 (c 0.50, MeOH). The ee was deter-
Angew. Chem. 1987, 99, 1323–1325; Vedejs, E.; Lee, N.;
Sakata, S. T. J. Am. Chem. Soc. 1994, 116, 2175–2176;
Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566–2587, and
546
mined according to Yao and Zeng7j to be >99.5% in
favor of the (S)-enantiomer.

2660
J. Riedner, P. Vogel / Tetrahedron: Asymmetry 15 (2004)2657–2660
references cited therein; Camps, P.; Gimenez, S. Tetrahe-
16. See for example: Reetz, M. T.; Schimossek, K. Chimia
1996, 50, 668–669; Goswami, A.; Mirfakhrae, K. D.;
Patel, R. N. Tetrahedron: Asymmetry 1999, 10, 4239;
Persson, B. A.; Larsson, A. L. E.; Le Ray, M.; Ba¨ckvall,
J.-E. J. Am. Chem. Soc. 1999, 121, 1645–1650; Dijksman,
A.; Elzinga, J. M.; Li, Y.-X.; Arends, I. W. C. E.; Sheldon,
R. A. Tetrahedron: Asymmetry 2002, 13, 879–884; Turner,
N. J. Curr. Opin. Chem. Biol. 2003, 14, 401–406; Turner,
N. J. Curr. Opin. Chem. Biol. 2004, 8, 114–119, and
references cited therein; Comasseto, J. V.; Andrade, L. H.;
Omori, A. T.; Assis, L. F.; Porto, A. L. M. J. Mol. Catal.
B: Enzym. 2004, 29, 55–61.
dron: Asymmetry 1996, 7, 1227–1234; Toke, L.; Bako, P.;
Keseru, G. M.; Albert, M.; Fenichel, L. Tetrahedron 1998,
54, 213–222; Um, P. J.; Drueckhammer, D. G. J. Am.
Chem. Soc. 1998, 120, 5605–5610; Burton, A. J.; Graham,
J. P.; Simpkins, N. S. Synlett 2000, 1640–1642; Vedejs, E.;
Kruger, A. W.; Lee, N.; Sakata, S. T.; Stec, M.; Suna, E. J.
Am. Chem. Soc. 2000, 122, 4602–4607; Calmes, M.; Glot,
C.; Michel, T.; Rolland, M.; Martinez, J. Tetrahedron:
Asymmetry 2000, 11, 737–741; Allan, G. R.; Carnell, A. J.;
Kroutil, W. Tetrahedron Lett. 2001, 42, 5959–5962;
´
Soladie-Cavallo, A.; Sedy, O.; Salisova, M.; Schmitt, M.
Eur. J. Org. Chem. 2002, 3042–3049; Kato, D.; Mitsuda,
S.; Ohta, H. Org. Lett. 2002, 4, 371–373; Clericuzio, M.;
Degani, I.; Dughera, S.; Fochi, R. Tetrahedron: Asym-
metry 2003, 14, 119–125; Kaku, H.; Okamoto, N.; Naka-
mura, A.; Tsunoda, T. Chem. Lett. 2004, 33, 516–517.
17. See for example: Luessen, B. J.; Gais, H.-J. J. Am. Chem.
Soc. 2003, 125, 6066–6067; Trost, B. M.; Krueger, A. C.;
Bunt, R. C.; Zambrano, J. J. Am. Chem. Soc. 1996, 118,
6520–6521; Trost, B. M.; Tsui, H.-C.; Toste, F. D. J. Am.
Chem. Soc. 2000, 122, 3534–3535.
15. See for example: Schlosser, M.; Limat, D. J. Am. Chem.
Soc. 1995, 117, 12342–12343; Prat, L.; Mojovic, L.;
Levacher, V.; Dupas, G.; Queguiner, G.; Bourguignon,
J. Tetrahedron: Asymmetry 1998, 9, 2509–2516; Prat, L.;
Dupas, G.; Duflos, J.; Queguiner, G.; Bourguignon, J.;
Levacher, V. Tetrahedron Lett. 2001, 42, 4515–4518.
18. See for example: Trost, B. M.; Tang, W.; Schulte, J. L.
Org. Lett. 2000, 2, 4013–4015.
19. Moreno-Vargas, A. J.; Vogel, P. Tetrahedron: Asymmetry
2003, 14, 3173–3176.
20. Henze, H. R.; Isbell, A. F. J. Am. Chem. Soc. 1954,
4152–4156.