Enantioselective protonation of prochiral enolates in the asymmetric synthesis of (S)-naproxen

Article abstract of DOI:10.1016/S0040-4039(03)00217-X

Racemic methyl, iso-propyl, and tert-butyl ester derivatives of naproxen were treated with achiral LDA base to give the corresponding prochiral enolates 2-Li, 3-Li, and 4-Li. Protonation of these enolates with novel chiral proton sources (S)-10 and (S,S)-11, containing the α-phenylethylamino group, proceeded in a highly enantioselective manner. Saponification of enantioenriched ester derivatives 2-4 afforded naproxen, (S)-1, with no loss of enantiopurity.

Full text of DOI:10.1016/S0040-4039(03)00217-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2023–2026
Enantioselective protonation of prochiral enolates in the
asymmetric synthesis of (S)-naproxen
Omar Mun˜oz-Mun˜iz and Eusebio Juaristi*
Departamento de Qu´ımica, Centro de Investigacio´n y de Estudios Avanzados del Instituto Polite´cnico Nacional,
Apartado Postal 14-740, 07000 Me´xico, D.F., Mexico
Received 14 January 2003; revised 20 January 2003; accepted 21 January 2003
Abstract—Racemic methyl, iso-propyl, and tert-butyl ester derivatives of naproxen were treated with achiral LDA base to give
the corresponding prochiral enolates 2-Li, 3-Li, and 4-Li. Protonation of these enolates with novel chiral proton sources (S)-10
and (S,S)-11, containing the a-phenylethylamino group, proceeded in a highly enantioselective manner. Saponification of
enantioenriched ester derivatives 2–4 afforded naproxen, (S)-1, with no loss of enantiopurity. © 2003 Published by Elsevier
Science Ltd.
The diastereoselective alkylation of chiral carbonyl
derivatives is now a well established strategy for asym-
metric carbonꢀcarbon bond formation.1 A conceptually
simple and potentially even more attractive methodol-
ogy consists in the desymmetrization of prochiral eno-
lates via enantioselective protonation with chiral acids.
Indeed, enantiotopic faces in a prochiral substrate may
be distinguished by chiral reagents to afford non-
racemic derivatives (Scheme 1).2–5
Finally, enantiopure (S)-naproxen was obtained by res-
olution of racemic naproxen, via fractional crystalliza-
tion of diastereomeric salts of (S)-a-phenylethyl-
amine.9,10 Table 2 presents the enantiomeric excesses of
naproxen samples isolated in first-crop crystals
obtained under different conditions. Particularly
efficient resulted the conditions specified in
(S)-2-(6-Methoxy-naphthalen-2-yl)propanoic
acid
[naproxen, (S)-1] is a powerful anti-inflammatory
agent, whose asymmetric synthesis continues to be a
challenging undertaking.6 We report in this letter the
results from the enantioselective protonation of prochi-
ral enolates 2–4-Li with novel chiral proton sources 5–8
(Scheme 2). Vedejs et al.4 have previously reported a
systematic study of the asymmetric protonation of 9-Li
with chiral aniline acids, to give predominantly (R)-1.
Scheme 1.
Racemic esters ( )-2, ( )-3, and ( )-4 were readily
prepared from commercially available racemic
naproxen, according to the reaction conditions summa-
rized in Scheme 3.7
Enantiomerically pure (S)-2, (S)-3, and (S)-4 were sim-
ilarly obtained by esterification of enantiomerically
pure (S)-naproxen.8 Table 1 summarizes the physical
properties of the enantiopure esters (S)-2–4.
Keywords: enantioselective protonations; chiral acids; resolution of
racemates; prochiral enolates; enolate desymmetrization; naproxen.
* Corresponding author. E-mail: juaristi@relaq.mx
Scheme 2.
0040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4039(03)00217-X

2024
O. Mun˜oz-Mun˜iz, E. Juaristi / Tetrahedron Letters 44 (2003) 2023–2026
Scheme 3.
Table 1. Esterification of (S)-naproxen [(S)-1] to give
enantiopure derivatives (S)-2–4a
Chart 1.
R
Yield (%)
[h]2D8
mp
thermore, the bulkier the substituent on the carboxylate
group the higher the enantioselectivity (compare entries
4 and 6 in Table 3, ee=90 and 93% for R=i-Pr and
t-Bu, with entry 2 in Table 3, ee=78% for R=CH3).14
Finally, verification of the absolute configuration and
isolation of the desired (S)-naproxen was achieved by
saponification under mild conditions (Eq. (1)).15,16
Me
i-Pr
t-Bu
95
69
22
+74.0
+22.4
+27.1
90–91
65–66
Wax
a For reaction conditions see Scheme 3 and Ref. 8.
entry 7, which afforded (S)-1 of 92% ee and in high
yield. This enantioenriched material was readily recrys-
tallized to give enantiopure (S)-1.
Racemic naproxen ester derivatives ( )-2, ( )-3, and
( )-4 (Scheme 3 and Table 1) were treated with the
achiral base LDA to give the corresponding prochiral
enolates 2-Li, 3-Li, and 4-Li, which were then reproto-
nated with the novel chiral Brønsted acids (S)-10 and
(S,S)-11 (Chart 1).11,12
(1)
In conclusion, racemic ester precursors 2–4 are easily
prepared by esterification of racemic naproxen, and
highly enantioselective protonation of prochiral eno-
lates 2–4-Li is possible with novel phenols (S)-10 and
(S,S)-11 as chiral proton sources. Since naproxen (1) is
readily recovered by saponification of enantioenriched
esters 2–4, an alternative procedure for the preparation
of (S)-naproxen is therefore available.
As anticipated,2–5 the above protocol afforded enan-
tiomerically enriched 2–4 (Table 3). C2-Symmetric phe-
nol (S,S)-11 proved to be a much better stereoinductor
(ee=78–93%) relative to (S)-10 (ee=69–76%).13 Fur-
Table 2. Resolution of racemic naproxen with (S)-a-phenylethylamine9
Entry
Equiv. (S)-a-PEA
Solvent
Yielda (%)
[h]2D8
eeb (%)
Major enantiomer
1
2
3
4
5
6
7
1.0
1.0
1.0
1.0
1.0
0.5
0.5
EtOH
49
50
48
47
50
82
90
+17.0
+22.3
+28.8
+17.8
+24.7
+42.0
+61.1
26
34
43
27
37
63
92
(S)
(S)
(S)
(S)
(S)
(S)
(S)
EtOH–H2O (1:1)
EtOH–H2O (7:3)
i-PrOH
i-PrOH–H2O (1:1)
i-PrOH–H2O (4:1)
i-PrOH–H2O (3:7)
a Calculated relative to the maximum theoretical yield.
b Determined by comparison of optical rotation with [h]D28=+65.9 (c 1.2, CHCl3) for enantiopure (S)-1.6a

O. Mun˜oz-Mun˜iz, E. Juaristi / Tetrahedron Letters 44 (2003) 2023–2026
2025
Table 3. Enantioselective protonation of prochiral enolates 2-Li, 3-Li, and 4-Li with chiral proton sources17
Entry
R
A*-H
Yield (%)
eea (%)
Major enantiomer
1
2
3
4
5
6
CH3
CH3
i-Pr
i-Pr
t-Bu
t-Bu
(S)-10
(S,S)-11
(S)-10
(S,S)-11
(S)-10
(S,S)-11
90
94
91
93
87
88
69
78
72
90
76
93
(S)
(S)
(S)
(S)
(S)
(S)
a Enantiomeric excess, determined by comparison of optical rotations with that of enantiopure standards (see text).
References
D. P. Tetrahedron Lett. 1998, 39, 8691; (f) Aboulhoda, S.
J.; Reiners, I.; Wilken, J.; Henin, F.; Martens, J.; Muzart,
J. Tetrahedron: Asymmetry 1998, 9, 1847; (g) Matsumoto,
K.; Tsutsumi, S.; Ihori, T.; Ohta, H. J. Am. Chem. Soc.
1990, 112, 9614; (h) Fujii, I.; Lerner, R. A.; Janda, K. D.
J. Am. Chem. Soc. 1991, 113, 8528; (i) Potin, D.;
Williams, K.; Rebek, J. Angew. Chem., Int. Ed. Engl.
1990, 29, 1420; (j) Roy, O.; Riahi, A.; He´nin, F.; Muzart,
J. Eur. J. Org. Chem. 2002, 3986; (k) Landais, Y.; Zekri,
E. Eur. J. Org. Chem. 2002, 4037.
1. (a) Eliel, E. L.; Koskimies, J. K.; Lohri, B.; Frazee, W. J.;
Morris-Natschke, S.; Lynch, J. E.; Soai, K. In Asymmet-
ric Reactions and Processes; Eliel, E. L.; Otsuka, S., Eds.;
American Chemical Society: Washington, 1982; (b)
Evans, D. A. In Asymmetric Synthesis; Morrison, J. D.;
Academic Press: New York, 1983–1984; Vol. 3, pp. 1–
110; (c) Seebach, D.; Juaristi, E.; Miller, D. D.; Schickli,
C.; Weber, T. Helv. Chim. Acta 1987, 70, 237; (d) Enders,
D.; Bettray, W.; Raabe, G.; Runsink, J. Synthesis 1994,
1322 and references cited therein; (e) Oppolzer, W. Pure
Appl. Chem. 1990, 62, 1241; (f) Seyden-Penne, J. In
Chiral Auxiliaries and Ligands in Asymmetric Synthesis;
Wiley: New York, 1995; (g) Juaristi, E.; Quintana, D.;
Balderas, M.; Garc´ıa-Pe´rez, E. Tetrahedron: Asymmetry
1996, 7, 2233; (h) Leo´n-Romo, J. L.; Virues, C. I.; Avin˜a,
J.; Regla, I.; Juaristi, E. Chirality 2002, 14, 144.
2. Basic concepts, see for example: (a) Juaristi, E. Introduc-
tion to Stereochemistry and Conformational Analysis;
Wiley: New York, 1991; (b) Eliel, E. L.; Wilen, S. H.;
Mander, L. N. Stereochemistry of Organic Compounds;
Wiley: New York, 1994; (c) Seebach, D. Angew. Chem.,
Int. Ed. Engl. 1988, 27, 1624; (d) Juaristi, E.; Beck, A. K.;
Hansen, J.; Matt, T.; Mukhopadhyay, T.; Simson, M.;
Seebach, D. Synthesis 1993, 1271.
3. Pioneering work: (a) Duhamel, L.; Plaquevent, J. C. J.
Am. Chem. Soc. 1978, 100, 7415; (b) Duhamel, L.;
Duhamel, P.; Launay, J.-C.; Plaquevent, J.-C. Bull. Soc.
Chim. Fr. 1984, 421; (c) Fehr, C.; Galindo, J. J. Am.
Chem. Soc. 1988, 110, 6909; (d) Fehr, C. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2566.
4. Mechanistic studies: (a) Vedejs, E.; Lee, N.; Sakata, S. T.
J. Am. Chem. Soc. 1994, 116, 2175; (b) Vedejs, E.;
Kruger, A. W.; Suna, E. J. Org. Chem. 1999, 64, 7863; (c)
Vedejs, E.; Kruger, A. W.; Lee, N.; Sakata, T.; Stec, M.;
Suna, E. J. Am. Chem. Soc. 2000, 122, 4602.
6. (a) Harrison, I. T.; Lewis, B.; Nelson, P.; Rooks, W.;
Roszkowoski, A.; Tomolonis, A.; Fried, J. H. J. Med.
Chem. 1970, 13, 203; (b) Riegl, J.; Maddox, M. L.;
Harrison, I. T. J. Med. Chem. 1974, 17, 377; (c) Gior-
dano, C.; Castaldi, G.; Uggeri, F. Angew. Chem., Int. Ed.
Engl. 1984, 23, 413; (d) Gu, Q.-M.; Chen, C.-S. Tetra-
hedron Lett. 1986, 27, 1763; (e) Giordano, C.; Castaldi,
G.; Cavicchioli, S.; Villa, M. Tetrahedron 1989, 45, 4243;
(f) Sonawane, H. R.; Bellur, N. S.; Ahuja, J. R.; Kulka-
rni, D. G. Tetrahedron: Asymmetry 1992, 3, 163; (g)
Manimaran, T.; Stahly, P. Tetrahedron: Asymmetry 1993,
4, 1949; (h) Huang, W.-C.; Tsai, S.-W.; Chang, C.-S. J.
Chin. Inst. Chem. Engrs. 1998, 29, 153.
7. Cf. March, J. Advanced Organic Chemistry; 3rd ed.;
Wiley: New York, 1985; p. 348.
8. Typical experimental procedure for the preparation of
enantiopure ester derivatives 2–4: To a 50 mL round-bot-
tom flask containing (S)-1 (0.5 g, 2.17 mmol) was added
30 mL of desired alcohol (MeOH, i-PrOH or t-BuOH),
and a catalytic amount of H2SO4. The reaction mixture
was filtered and concentrated in a rotary evaporator and
extracted with CH2Cl2 (3×15 mL). The combined organic
layers were washed with water (2×5 mL) and brine (1×10
mL), and dried with Na2SO4. Removal of the solvent left
a residue that was recrystallized from hot MeOH:H2O
(3:7).
1
(S)-2 H NMR (CDCl3): l 1.57 (d, J=6.9 Hz, 3H), 3.65
5. Salient examples: (a) Ishihara, K.; Nakamura, S.;
Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996,
118, 12854; (b) Kosugi, H.; Hoshino, K.; Uda, H. Tetra-
hedron Lett. 1997, 38, 6861; (c) Asensio, G.; Aleman, P.;
Gil, J.; Dommingo, L. R.; Medio-Simon, M. J. Org.
Chem. 1998, 63, 9342; (d) Yanagisawa, A.; Watanabe, T.;
Kikuchi, T.; Yamamoto, H. J. Org. Chem. 2000, 65,
2979; (e) Takeuchi, S.; Nakamura, Y.; Ohgo, Y.; Curran,
(s, 3H), 3.85 (q, J=7.0 Hz, 1H), 3.89 (s, 3H), 7.02–7.89
(m, 6H). 13C NMR (CDCl3): l 18.6, 45.4, 52.0, 55.3,
105.7, 118.9, 125.9, 126.1 127.1, 128.9, 129.2, 133.7,
135.6, 157.6, 174.9.
1
(S)-3 H NMR (CDCl3): l 1.11 (d, J=6.3 Hz, 3H), 1.25
(d, J=6.3 Hz, 3H), 1.54 (d, J=7.1 Hz, 3H), 3.80 (q,
J=7.1 Hz, 1H), 3.89 (s, 3H), 5.01 (sept, J=6.3 Hz, 1H),
7.04–7.73 (m, 6H). 13C NMR (CDCl3): l 18.7, 21.8, 22.6,

2026
O. Mun˜oz-Mun˜iz, E. Juaristi / Tetrahedron Letters 44 (2003) 2023–2026
45.7, 55.3, 68.0, 105.7, 119.0, 125.9, 126.3 127.1, 129.1,
(CDCl3): l 1.29 (d, J=7.2 Hz, 3H), 1.37 (d, J=7.2 Hz,
3H), 3.58 (q, J=7.2 Hz, 1H), 3.70 (dd, J=11.9 Hz,
J=6.9 Hz, 2H) 4.21 (q, J=7.1 Hz, 1H), 7.11–7.55 (m,
14H), 9.37 (bs, 1H). 13C NMR (CDCl3): l 21.9, 22.1,
40.6, 40.8, 49.9, 50.2, 117.6, 120.4, 121.9, 127.5, 129.1,
129.2, 130.4, 142.6, 155.9, 179.8.
129.4, 133.8, 136.0, 157.7, 174.3.
1
(S)-4 H NMR (CDCl3): l 1.39 (s, 9H), 1.52 (d, J=7.1
Hz, 3H), 3.74 (q, J=7.1 Hz, 1H), 3.90 (s, 3H), 7.09–7.78
(m, 6H). 13C NMR (CDCl3): l 18.6, 28.2, 46.3, 55.3, 68.1,
80.6, 105.6, 118.9, 125.7, 126.3, 127.1, 129.1, 129.4, 132.5,
136.4, 157.6, 174.1.
13. For a discussion on the benefits of using C2-symmetric,
chiral ligands in asymmetric synthesis, see: Whitesell, J.
K. Chem. Rev. 1989, 89, 1581.
14. It is anticipated that, by analogy with naproxen amide
enolate 9-Li,4 the Z configured enolates 2–4-Li are
formed upon treatment of 2–4 with LDA.
15. The absolute (S) configuration in recovered esters 2–4
(Table 3) indicates like16 stereoinduction in the proton
transfer from (S)-10 and (S,S)-11 to prochiral enolates
2–4-Li.
16. For a definition of the like/unlike stereochemical descrip-
tors, see: Seebach, D.; Prelog, V. Angew. Chem., Int. Ed.
Engl. 1982, 21, 654.
17. General procedure for the enantioselective protonation of
rac 2–4 with chiral proton sources (S)-10, and (S,S)-11. A
solution of (i-Pr)2NH (1.1 equiv.) in toluene was cooled
to 0°C before the slow addition of BuLi (1.1 equiv., ca.
1.8 M in hexane). The resulting solution was stirred for
30 min., and then cooled to −78°C before the dropwise
addition of rac-2–4 (1.0 equiv.) in toluene (10 mL).
Stirring was continued for 1 h at −78°C in order to secure
the complete formation of the corresponding enolate. The
protonation source (S)-10 or (S,S)-11 (1.2 equiv.) in
toluene was then added dropwise via syringe, and the
reaction mixture was stirred at −78°C for 30 min, at
ambient temperature for 5 min, and finally cooled at
−78°C before it was quenched by the addition of satu-
rated aqueous NH4Cl solution and extracted with
CH2Cl2 (3×25 mL). The combined extracts were washed
with water and brine, and dried over anhydrous Na2SO4,
filtered and concentrated at reduced pressure. The residue
was purified by flash chromatography using hexanes–
ethyl acetate (7:3) as eluent.
9. Typical experimental procedure for the resolution of
racemic naproxen [( )-1] with (S)-h-phenylethylamine. To
a 25 mL three-necked flask containing ( )-1 (1.0 g, 4.34
mmol) was added 10 mL of a mixture of solvents [i-
PrOH:H2O (7:3)] and heated at 70°C for 30 min. Subse-
quently, slow addition of (S)-a-PEA (0.26 g, 2.17 mmol)
dissolved in 5 mL of the mixture used was carried out
with continued heating for a period of 30 min. Finally,
the reaction mixture was brought without stirring ring to
room temperature. The diastereoisomeric salts were
recrystallized [i-PrOH:H2O (7:3)]. A solution of the
diastereomerically pure salt was treated with HCl 10%
and extracted with CH2Cl2 (3×20 mL), washed with
water, brine (1×10 mL), dried with Na2SO4 and concen-
trated to afford 0.45 g (90% yield) of (S)-1. [h]2D8=+61.1
(c 1.5, CHCl3), 92% ee.
10. (a) For a review on the use of a-phenylethylamine as
resolving agent, see: Juaristi, E.; Escalante, J.; Leo´n-
Romo, J. L.; Reyes, A. Tetrahedron: Asymmetry 1998, 9,
715; (b) See also: Reyes, A.; Juaristi, E. Synth. Commun.
1995, 25, 1053.
11. For a review on the use of a-phenylethylamine as chiral
auxiliary, see: Juaristi, E.; Leo´n-Romo, J. L.; Reyes, A.;
Escalante, J. Tetrahedron: Asymmetry 1999, 10, 2441.
12. 2-(2-Hydroxyphenyl)-N-(1-phenylethyl)acetamide, (S)-10.
Mp 105°C. [h]2D8=−34.7 (c 1.1 CHCl3). 1H NMR
(CDCl3): l 1.42 (d, J=7.3 Hz, 3H), 3.55 (dd, J=11.6 Hz,
J=4.1 Hz, 2H), 5.04 (m, 1H), 6.89–7.32 (m, 9H), 9.96
(bs, 1H). 13C NMR (CDCl3): l 21.8, 40.6, 49.6, 117.6,
120.5, 121.7, 126.1, 127.5, 128.8, 129.1, 130.9, 142.5,
155.8, 177.7.
2-(2-Hydroxyphenyl)-N,N-bis-(1-phenylethyl)acetamide,
(S,S)-11. Oil, [h]2D8=−75.4 (c 1.0 CHCl3). 1H NMR