Asymmetric alcoholysis of 2-phenyl-5(4H)-oxazolones by the catalytic mixture of cyclo[(S)-His-(S)-Phe] with chiral auxiliaries

Article abstract of DOI:10.1016/S0957-4166(99)00577-7

Some derivatives of dipeptides containing a His residue catalyzed the ring opening of 2-phenyl-4-benzyl-5(4H)-oxazolone by methanol. The mixture of cyclo[(S)-His-(S)-Phe] (CHP) with chiral auxiliaries which possess both a hydrogen-bond donor and a hydroge

Full text of DOI:10.1016/S0957-4166(99)00577-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4715–4728
Asymmetric alcoholysis of 2-phenyl-5(4H)-oxazolones by the
catalytic mixture of cyclo[(S)-His-(S)-Phe] with chiral auxiliaries
Lunjia Xie,a Wenting Hua,a,∗ Albert S. C. Chan b and Yun-Chang Leung b
aDepartment of Chemistry, Peking University, Beijing 100871, China
bOpen Laboratory of Chirotechnology and Department of Applied Biology and Chemical Technology,
The Hong Kong Polytechnic University, Hong Kong, China
Received 25 October 1999; accepted 30 November 1999
Abstract
Some derivatives of dipeptides containing a His residue catalyzed the ring opening of 2-phenyl-4-benzyl-5(4H)-
oxazolone by methanol. The mixture of cyclo[(S)-His-(S)-Phe] (CHP) with chiral auxiliaries which possess both
a hydrogen-bond donor and a hydrogen-bond acceptor was a more effective and enantioselective catalyst than
the CHP alone. The influence of racemic and the two enantiomerically pure auxiliaries on the cyclo[(S)-His-(S)-
Phe]-catalyzed alcoholysis of the 5(4H)-oxazolone was different. A mixture of CHP with L-diisopropyl tartrate
catalyzed the enantioselective ring opening of 2-phenyl-4-benzyl-5(4H)-oxazolone by methanol, ethanol and n-
butanol, preferentially affording the N-benzoyl-L-phenylalaninates (20–39% e.e.). © 2000 Elsevier Science Ltd.
All rights reserved.
1. Introduction
The importance of optically active natural and unnatural α-amino acids has prompted the development
of practical methods for their preparation in an enantiomerically pure form of either configuration. An
important and interesting method for the preparation of optically active L-α-amino acids was the lipase-
catalyzed dynamic kinetic resolution of racemic 5(4H)-oxazolones by alcohols.1 However, in general,
the inherent disadvantages of enzymatic methods such as the specificity and instability of enzymes are
difficult to overcome. Narrow substrate tolerance and selection of L-configured enantiomers limit the
scope of the enzymatic method.
Nonenzymatic catalysts are often used for a wider scope of substrates. Moreover, desired configuration
and high enantioselectivity of the product may be achieved by the proper design of the nonenzymat-
ic catalysts. Nonenzymatic catalytic enantioselective hydrolysis2 and stoichiometric enantioselective
∗
Corresponding author.
0957-4166/99/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00577-7
tetasy 3211

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alcoholysis3 of racemic 5(4H)-oxazolones have been reported. Because 5(4H)-oxazolones are easily
hydrolyzed without catalysts, we have sought to devise a method for the catalytic enantioselective
alcoholysis of racemic 5(4H)-oxazolones. We found that cinchona alkaloids could be used as nonen-
zymatic catalysts for enantioselective methanolysis of 2-phenyl-5(4H)-oxazolones,4 but derivatives of
the hydroxyl at C9 of cinchona alkaloids showed almost no catalytic activity.5 Fu et al. also investigated
enantioselective methanolysis of 2-phenyl-5(4H)-oxazolones catalyzed by a planar-chiral derivative of
4-(dimethylamino)pyridine.6
Since lipases catalyze ring opening of 5(4H)-oxazolones by alcohols1 and lipases contain essential
histidine residues in their active sites,7 we used derivatives of dipeptides containing a histidine residue
as nonenzymatic catalysts for the enantioselective alcoholysis of 2-phenyl-4-benzyl-5(4H)-oxazolone.
Indeed, dipeptides and cyclo dipeptides, which contain a histidine residue, have been used for hydrolysis
of p-nitrophenyl carboxylate8 and for the asymmetric hydrocyanation of benzaldehyde.9 More rigid
cyclo dipeptides gave higher enantiomeric excesses of cyanohydrins than linear dipeptides.9a Of the
cyclo dipeptides, cyclo[(S)-His-(S)-Phe] (CHP) or cyclo[(R)-His-(R)-Phe] is the most enantioselective
catalyst reported by Inoue et al. and others.9 Although CHP and its enantiomer has proved to be
effective in the production of optically active cyanohydrins from aromatic aldehydes and HCN, to date
no satisfactory explanations for the enantioselectivity and autocatalysis exist.10 The structure of active
CHP and the structure of the complexes of CHP with cyanohydrins are unclear.10b We have proposed a
new mechanistic model for the asymmetric addition of HCN to aldehydes catalyzed by CHP based on
known results. We have presented the possible structure of active CHP as a catalyst and presumed the
structure of the complex of CHP with a cyanohydrin as a more effective and enantioselective catalyst to
explain autocatalysis and enantioselective autoinduction.11
Here, we report the use of linear dipeptides and cyclo dipeptides containing histidine residues as
catalysts for the alcoholysis of 2-phenyl-4-benzyl-5(4H)-oxazolone, and present an application of the
mechanistic model for the asymmetric hydrocyanation of aldehyde11 to catalytic alcoholysis of the
5(4H)-oxazolone by the mixture of CHP with chiral auxiliaries. We also try to explain why the proposed
complexes of CHP with auxiliaries are more effective and enantioselective catalysts than CHP.
2. Results and discussion
2.1. Derivatives of dipeptides as catalysts
(±)-2-Phenyl-4-benzyl-5(4H)-oxazolone [(±)-1] was selected as the substrate for our initial studies,
since the configuration of product 2 could be deduced by comparing the specific rotation of 2 to that of au-
thentic 2 (R or S) and the e.e. of 2 and its configuration could be determined by capillary electrophoresis.12
Derivatives of dipeptides (3–8) catalyzed the ring opening of (±)-1 using methanol as the nucleophile
in organic solvents. The reactions carried out in the appropriate solvent [100 mL/substrate (g)] by using
the following mol ratio: substrate:methanol:catalyst=1:6.2:0.5–0.6. The percentage conversion of 1 into
2 was determined from the 1H NMR spectra of the products or deduced from the TLC by comparing the
reaction mixture with the mixture of known mol ratios of 1 and 2 at the same molar concentration. The
derivatives of dipeptides which were soluble in organic solvents (4–6) were more effective catalysts than
insoluble derivatives of dipeptides (3, 7 and 8) (see Scheme 1 and Table 1).
Since cyclo[(S)-His-(S)-Phe] (CHP) or its enantiomer were the most effective and enantioselective
catalysts of the derivatives of dipeptides for the asymmetric hydrocyanation of aldehydes, this suggested
that CHP 8 might be the most effective and enantioselective catalyst for ring opening of (±)-1. However,

L. Xie et al. / Tetrahedron: Asymmetry 10 (1999) 4715–4728
4717
Scheme 1.

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L. Xie et al. / Tetrahedron: Asymmetry 10 (1999) 4715–4728
Table 1
Methanolysis of (±)-1 by derivatives of dipeptides
results showed that CHP (8) was less effective and enantioselective than linear dipeptides (4, 5 and 6).
We, therefore, studied the mechanistic model for the asymmetric addition of HCN to aldehydes catalyzed
by CHP based on known results. We also analyzed the reasons why CHP was not an effective and
enantioselective catalyst for ring opening of (±)-1 by methanol. In addition, we devised the mixture
of CHP with chiral auxiliaries as catalysts for the alcoholysis of (±)-1.

L. Xie et al. / Tetrahedron: Asymmetry 10 (1999) 4715–4728
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2.2. Mixture of CHP with chiral auxiliaries as catalysts
From the studies of the mechanistic models for the asymmetric addition of HCN to aldehydes catalyzed
by CHP, we postulated11 that part of the structure of active CHP in solid state was A and the structure
of the complex of CHP with a cyanohydrin was B, and a new mechanistic model for asymmetric
addition of HCN to benzaldehyde is shown in Fig. 1. By an application of these ideas to the catalytic
alcoholysis of (±)-1 by CHP, methanolysis of (±)-1 is catalyzed by an active part of the hydrogen-
bonded polymer of CHP (Fig. 2). Unlike a cyanohydrin which broke the hydrogen bonds of the CHP
polymer13 and formed the catalytic complex with CHP, the product of methanolysis of (±)-1, N-benzoyl
phenylalanine methyl ester (2, R0=Me), could not break the hydrogen bonds of the CHP polymer, for
2 might exist as either a trans C or cis-dimer D or E instead (Fig. 3) of forming a complex with CHP.
We supposed that the catalytic activity of CHP could be liberated by breaking the hydrogen bond of
the CHP polymer and the enantioselectivity of CHP could be enhanced by forming complexes between
CHP and chiral auxiliaries which possessed both a hydrogen-bond donor and a hydrogen-bond acceptor
like cyanohydrins. Therefore, various auxiliaries of (±)-1, including A1 (L-diisopropyl tartrate), A2 (D-
diisopropyl tartrate), A3 (L-diethyl tartrate), A4 [(±)-ethyl lactate], A5 [(S)-ethyl lactate], A6 [(R)-methyl
lactate], A7 [(±)-lactic acid], A8 (L-tartaric acid), A9 (L-proline), A10 [(±)-proline], A11 (L-menthol),
A12 [(±)-menthol], A13 (benzyloxycarbonyl-L-leucyl-glycine ethyl ester), A14 (L-arginine·HCl), A15
(L-leucine), A16 [(±)-leucine], A17 (phthalimide), A18 (benzoic acid) and A19 [(4S)-2-(2-hydroxyl
phenyl)-4-(2-methylpropyl)oxazoline]. The structure F (Fig. 4) represents the possible complex of CHP
with a chiral auxiliary (α-hydroxyl carboxylic ester).
The results of preliminary investigations on the methanolysis of (±)-1 catalyzed by the mixture of
CHP and an auxiliary are summarized in Table 2 (CHP:auxiliary=1:4) and Table 3 (CHP:auxiliary=1:1).
Among the 19 auxiliaries examined, L-diisopropyl tartrate (A1) was best suited for further investigation
(see Tables 4 and 5). From Tables 2–5, the mol ratio of substrate, methanol and CHP was 1, 6.2 and 0.5.
The results in Tables 2 and 3 support our arguments: the catalytic activity of CHP could be liberated by
breaking the hydrogen bonds of the CHP polymer and the enantioselectivity of CHP could be enhanced
by forming the proposed complexes between CHP and chiral auxiliaries which possess both a hydrogen-
bond donor and a hydrogen-bond acceptor.
The percentage conversion of 1 into 2 was about 50% at 15–16°C for 2 days with the mixture of
CHP and L-diisopropyl tartrate (A1), while the percentage conversion was less than 10% at 13–14°C
for 4 days with only CHP. The conversion of the reaction catalyzed by the mixture of CHP and A1
was almost complete at 15–16°C for 6 days and the enantiomeric excess of the product 2 was 27%,
whereas the conversion of the reaction catalyzed by only CHP was 75% at 25°C for 4 days with almost
no enantioselectivity (see entries 21, 22, 35 and 36).
The influence of two enantiomeric auxiliaries on CHP-catalyzed methanolysis of (±)-1 was different.
The enantioselectivity of the reaction catalyzed by the mixture of CHP and L-diisopropyl tartrate was
27% e.e., whereas that of the reaction catalyzed by the mixture of CHP and D-diisopropyl tartrate was
only 2% e.e. (see entries 21 and 23). Because the configuration of C2 and C3 of L-diisopropyl tartrate is R,
the hydroxyl group at C2 and the carbonyl group at C1 of L-diisopropyl tartrate may form hydrogen bonds
with the carbonyl group at the phenylalanine residue and the amido NH group at the histidine residue of
cyclo[(S)]His-(S)-Phe] (CHP), respectively, for the steric hindrance of the phenyl group at CHP with the
R group at L-diisopropyl tartrate (see structure F (Fig. 4)). On the contrary, the configuration of C2 and
C3 of D-diisopropyl tartrate is S. The D-diisopropyl tartrate may not form two similar hydrogen bonds
with CHP because of steric hindrance. This explains why L-diisopropyl tartrate was a better auxiliary
than D-diisopropyl tartrate on enantioselectivity and rate of reaction.

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L. Xie et al. / Tetrahedron: Asymmetry 10 (1999) 4715–4728
Fig. 1.

L. Xie et al. / Tetrahedron: Asymmetry 10 (1999) 4715–4728
4721
Fig. 2.
Fig. 3.
For the same reason, it is difficult for (S)-ethyl lactate to form the two hydrogen bonds with CHP.
Therefore, the percentage conversion was less than 10% at 15–16°C for 8 days with (S)-ethyl lactate
(A5) as an auxiliary. But the percentage conversion was more than 50% with (±)-ethyl lactate (A4)
because (±)-ethyl lactate contained (R)-ethyl lactate which could form the two hydrogen bonds with
CHP (see entries 25 and 26). (R)-Methyl lactate (A6) or (±)-lactic acid (A7) were also better auxiliaries
than A5 (see entries 27 and 28).
L-Amino acids with aliphatic side chains such as L-proline (A9) and L-leucine (A15) may form two
hydrogen bonds with CHP in either the G or H structure (complex of CHP with A15). R and S isomers
of racemic amino acids with aliphatic chains might form cyclic dimers (I) by two hydrogen bonds (Fig.
5).

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L. Xie et al. / Tetrahedron: Asymmetry 10 (1999) 4715–4728
Fig. 4.
The L-amino acids were better auxiliaries than their racemates for methanolysis of (±)-1 catalyzed by
CHP with auxiliaries because the L-amino acids might form complexes with CHP (see entries 30, 31 and
40–43).
A13 and A19 might also form complexes with CHP (see structures J and K (Fig. 6)). The complexes
were better catalysts than CHP (see entries 35, 36, 38 and 47). A18 or A19 could not catalyze
methanolysis of (±)-1, but the mixture of CHP with A18, A19 or both could catalyze the reaction and
were more effective and enantioselective than CHP. The auxiliaries, which could not form stable cyclic
complexes with CHP (A11, A12 and A17), had little influence on catalytic activity of CHP. Unlike A18
or A19, A1 was also a catalyst. The results of methanolysis of (±)-1 by A1 and/or other catalysts are
shown in Table 4.
In order to improve enantioselectivity, we used less acidic and more steric alcohols (ethanol or n-
BuOH) as the nucleophile for the ring opening of (±)-1 utilizing the mixture of CHP and A1 as the
catalyst. The percent enantiomeric excess of 2 (R0=Et) was 39% e.e. for ethanol and that of 2 (R0=n-Bu)
was 35% e.e. for n-BuOH.
The imidazole group on the CHP and in other dipeptides containing His residue acts as either base or
nucleophilic catalyst for the ring opening of 2-phenyl-4-benzyl-5(4H)-oxazolone 1, because imidazole
can take part in either base or nucleophilic catalysis for an ester hydrolysis or acyl transfer depending
on the structure of the ester7 and 1 is an activated ester. The role of the imidazole group in either base
or nucleophilic catalysis also depends on the structure of a nucleophilic agent. The imidazole group may
act as a more effective base catalyst in the methanolysis of 1, although the imidazole group can still take
part in nucleophilic catalysis in the reaction. The nucleophilic catalysis becomes relatively more effective

L. Xie et al. / Tetrahedron: Asymmetry 10 (1999) 4715–4728
4723
Table 2
Methanolysis of (±)-1 by mixture of CHP and auxiliaries (CHP/aux.=1/4)
as the base catalysis is inhibited by using less acidic and more steric alcohols as nucleophiles. So, the
enantioselectivity of the catalysis increases (see Table 5). The enantioselectivity of products depends on
the relative effectiveness of nucleophilic or base catalysis.
3. Conclusion
Derivatives of dipeptides containing a His residue can be used to catalyze the alcoholysis of 2-phenyl-
4-benzyl-5(4H)-oxazolone. The rate of reaction depends on the solubility of the dipeptides. Mixtures of
cyclo[(S)-His-(S)-Phe] (CHP) with auxiliaries are more effective and enantioselective catalysts than the
CHP alone.
4. Experimental
4.1. General
Melting points are uncorrected. Optical rotations were measured on a Perkin–Elmer 241 polarimeter
1
with a 1 dm cell. H NMR spectra were recorded on a Bruker AKX-400 (400 MHz) spectrometer. IR
spectra were recorded on a Bruker Vector Series spectrometer.

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L. Xie et al. / Tetrahedron: Asymmetry 10 (1999) 4715–4728
Table 3
Methanolysis of (±)-1 by a mixture of CHP and auxiliaries (CHP/aux.=1)
Table 4
Methanolysis of (±)-1 by a catalyst and/or A1
For the determination of e.e., the N-benzoyl-phenylalanine esters were first hydrolyzed into N-benzoyl-
phenylalanine by NaOH and then analyzed by aqueous capillary electrophoresis using β-CD as chiral
selector.12

L. Xie et al. / Tetrahedron: Asymmetry 10 (1999) 4715–4728
4725
Table 5
Alcoholysis of (±)-1 by the complex of CHP and A1 in toluene
Fig. 5.
Fig. 6.

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L. Xie et al. / Tetrahedron: Asymmetry 10 (1999) 4715–4728
4.2. (±)-2-Phenyl-4-benzyl-5(4H)-oxazolone 1
Compound 1 was prepared from N-benzoyl-phenylalanine according to literature procedure.2a Yield
80%; mp: 66–68°C (lit.:2a mp: 70–71°C). IR (cm−1): 1812, 1754. 1H NMR (ppm, CDCl3): δ 3.20 (dd,
1H, J=6.4, 14 Hz), 3.40 (dd, 1H, J=5.2, 14 Hz), 4.71 (dd, 1H, J=5.2, 6.4 Hz), 7.22–7.29 (m, 5H), 7.44
(m, 2H), 7.55 (m, 1H), 7.94 (m, 2H).
4.3. N-Tosyl-(S)-prolyl-(S)-histidine methyl ester 4
(S)-Histidine methyl ester dihydrochloride (100 mg) was suspended in CHCl3 (1.5 mL) and Et3N
(0.125 mL) was added. The mixture was stirred and cooled in an ice–salt bath (−5°C). A solution of
N-tosyl-(S)-prolyl chloride14 (120 mg) in CHCl3 (5 mL) was added dropwise and Et3N (0.06 mL) was
added again. The mixture was stirred overnight. CHCl3 (5 mL) was added and the reaction mixture was
extracted with water then with aqueous ammonia (0.05 mol dm−3) and finally with water. The organic
layer was dried over anhydrous MgSO4 and concentrated in vacuum to give 170 mg of 4 as an oily solid.
Crystallization from benzene–petroleum ether (30–60°C) gave 110 mg (yield 63.4%) of white solid; mp:
57.5–59.5°C. IR (cm−l): 3399, 2955, 1745, 1672, 1347, 1160, and 1092. 1H NMR (ppm, CDCl3): δ 1.6
(m, 1H), 1.70 (m, 1H), 1.86 (m, 1H), 2.03 (m, 1H), 2.44 (s, 3H), 3.13–3.27 (m, 3H), 3.62 (m, 1H), 3.75
(s, 3H), 4.31 (dd, 1H, J=3.1, 8.7 Hz), 4.80 (m, 1H), 6.98 (s, 1H), 7.36 (s, 1H), 7.37 (d, 2H, J=8.1 Hz),
7.69 (s, 1H), 7.86 (d, 2H, J=8.2 Hz), 8.54 (d, 1H, J=8 Hz). FABMS 421 [M+H]+.
4.4. Benzyloxycarbonyl-(S)-alanyl-(S)-histidine methyl ester 5
Compound 5 was prepared from benzyloxycarbonyl-(S)-alanine-p-nitrophenyl ester and (S)-histidine
methyl ester dihydrochloride according to the literature.15 Yield 53%; mp: 164–166 (lit.:9c mp: 168–169).
1
IR (cm−1): 3379, 3248, 2990, 2852, 1732, 1702, 1649, 1566, 1505, 1456, 1379, 1340, 1291, 1235. H
NMR (ppm, CDCl3): δ 1.41 (d, 3H, J=7.2 Hz), 3.19 (m, 2H), 3.74 (s, 3H), 4.25 (dq, 1H, J=6.8, 7 Hz),
4.80 (m, 1H), 5.09 (d, 1H, J=12.4 Hz), 5.13 (d, 1H, J=12.2 Hz), 5.53 (d, 1H, J=6.4 Hz), 6.82 (s, 1H), 7.33
(m, 6H), 7.7 (s, 1H).
4.5. Benzyloxycarbonyl-(S)-phenylalanyl-(S)-histidine methyl ester 6
Compound 6 was prepared from benzyloxycarbonyl-(S)-phenylalanine-p-nitrophenyl ester and (S)-
histidine methyl ester dihydrochloride according to the literature.15 Yield 76%; mp: 128–138°C (lit.:15
yield 39%; mp: 146–154°C; lit.:9c yield 77%; mp: 114–116°C). IR (cm−1): 3312, 3013, 2952, 2854,
1743, 1699, 1648, 1532, 1440, 1391, 1256, 1215. 1H NMR (ppm, CDCl3): δ 2.95–3.15 (m, 4H), 3.68 (s,
3H), 4.39 (m, 1H), 4.75 (m, 1H), 5.07 (s, 2H), 5.43 (d, 1H, J=7.2 Hz), 6.72 (s, 1H), 7.18 (m, 11H, ArH
and CONH), 7.47 (s, 1H), 8.1 (bs, 1H).
4.6. (3S,6S)-3-(4-Imidazolylmethyl)-6-methylpiperazine-2,5-dione 7
Compound 7 was prepared from 5 according to the literature.15 Yield 79%; mp: 224–235°C (lit.:9c mp:
245–250°C). IR (cm−1): 3320, 3127, 2982, 2840, 1664, 1423, and 1312. 1H NMR (ppm, (CD3)2SO): δ
1.16 (d, 3H, J=7.2 Hz), 3.08 (m, 2H), 3.90 (q, 1H, J=6.9 Hz), 4.24 (t, 1H, J=5.42 Hz), 7.34 (s, 1H), 8.12
(s, 1H), 8.27 (s, 1H), 8.93 (s, 1H), 14.16 (bs, 2H).

L. Xie et al. / Tetrahedron: Asymmetry 10 (1999) 4715–4728
4727
4.7. (3S,6S)-3-Benzyl-6-(4-imidazolylmethyl)piperazine-2,5-dione 8
Compound 8 was prepared from 6 according to the literature.9b Yield 76%; mp: 249–252 (dec.) (lit.:9b
30
25
248–251°C), [α] −65.8 (c=0.52, AcOH) [lit.:9b [α] −65.2 (c=1.97, AcOH)]. IR (cm−1): 3424, 3195,
D
D
1673, 1458, and 1339. 1H NMR (ppm, (CD3)2SO): δ 1.57 (dd, 1H, J=9.1, 14.5 Hz), 2.55 (dd, 1H, J=3.6,
14.5 Hz), 2.81 (dd, 1H, J=4.9, 13.5 Hz), 2.87 (dd, 1H, J=4.7, 13.5 Hz), 3.84 (d, 1H, J=8.9 Hz), 4.14 (s,
1H), 6.61 (s, 1H), 7.15 (d, 2H, J=6.9 Hz), 7.23 (m, 1H), 7.3 (t, 2H, J=7 Hz), 7.57 (s, 1H), 7.79 (s, 1H),
8.11 (s, 1H), 11.90 (bs, 1H, NH). FABMS 285 [M+H]+.
4.8. Benzyloxycarbonyl-L-leucyl-glycine ethyl ester A13
Et3N (0.49 mL) was added to a suspension of glycine ethyl ester hydrochloride (0.5 g) in CHCl3
(10 mL), and stirred at 14°C for 10 min. Benzyloxycarbonyl-(S)-leucyl-p-nitrophenyl ester (1.38 g),
dissolved in CHCl3 (9 mL), was added dropwise and Et3N (0.5 mL) was added again. The mixture was
stirred at 14°C for 11 h, and imidazole (0.050 g) was added. Then the mixture was stirred for 23 h,
and CHCl3 (5mL) was added. The solution was extracted with water, aqueous ammonia, water, diluted
hydrochloric acid and water. The organic phase was dried over anhydrous MgSO4 and concentrated in
vacuum to gave 1.31 g (yield ∼100%) of colorless crystals, mp: 100–101°C. IR (cm−1, Nicolet MX-S
spectrometer): 3300, 3080, 2960, 2920, 2880, 1720, 1680, 1620, 1540, 1500, 1470, 1360, 1300, 1230,
1
1040. H NMR (ppm, CDCl3): δ 0.94 (d, 6H, J=6 Hz), 1.27 (t, 3H, J=7.2 Hz), 1.54 (m, 1H), 1.67 (m,
2H), 3.98 (s, 2H), 4.20 (q, 2H, J=7.2 Hz), 4.26 (s, 1H), 5.09 (d, 1H, J=12.2 Hz), 5.12 (d, 1H, J=12.2 Hz),
5.30 (d, 1H, J=8.1 Hz), 6.66 (s, 1H), 7.26–7.37 (m, 5H).
4.9. Methanolysis of (±)-1 by dipeptide derivatives
To the solution of (±)-1 (10 mg) in CHCl3 (1 mL) was added benzyloxycarbonyl-(S)-phenylalanyl-
(S)-histidine methyl ester (10 mg). The mixture was stirred at 20°C. The progress of the reaction was
monitored by TLC using the solvent system ethyl acetate:hexane (2:3). The products were separated and
purified by preparative TLC; 6% e.e. of (S)-2 was obtained.
4.10. Enantioselective methanolysis of (±)-1 by CHP with auxiliaries
To a suspension of CHP (6 mg) in toluene (1 mL) was added L-(±)-diisopropyl tartrate (ca. 0.017
mL). The mixture was stirred at room temperature (15.5°C) for 1 h and 40 min. Then to the mixture were
added (±)-1 (10 mg) and MeOH (0.01 mL). The reaction mixture was stirred for 6 days. The product,
purified by preparative TLC, gave 27% e.e. of (S)-2.
Acknowledgements
We gratefully acknowledge Dr. Zhao Gang of Prof. Li Chongxi’s research group for a gift of Boc-
L-His-D-TrpOMe 3 and thank Mr. Wu Haichen for the synthesis of (4S)-2-(2-hydroxylphenyl)-4-(2-
methylpropyl)oxazoline (A19). Partial financial support from the Hong Kong Polytechnic University
is appreciated.

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L. Xie et al. / Tetrahedron: Asymmetry 10 (1999) 4715–4728
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