Horse liver esterase catalyzed enantioselective hydrolysis of N,O- diacetyl-2-amino-1-arylethanol

Article abstract of DOI:10.1016/S0957-4166(97)00610-1

N,O-Diacetyl-2-amino-1-arylethanol can be efficiently resolved by horse liver esterase (HLE). A remarkable organic co-solvent effect on the enantioselectivity of HLE was observed.

Full text of DOI:10.1016/S0957-4166(97)00610-1

Pergamon
Tetrahedron: Asymmetry 9 (1998) 169–178
Horse liver esterase catalyzed enantioselective hydrolysis of
N,O-diacetyl-2-amino-1-arylethanol
Taoues Laïb, Jamal Ouazzani and Jieping Zhu ∗
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France
Received 12 November 1997; accepted 20 November 1997
Abstract
N,O-Diacetyl-2-amino-1-arylethanol can be efficiently resolved by horse liver esterase (HLE). A remarkable
organic co-solvent effect on the enantioselectivity of HLE was observed. © 1998 Elsevier Science Ltd. All rights
reserved.
Many substituted 2-amino-1-arylethanols are of great pharmaceutical importance. For example, (R)-
(−)-terbutaline 11 is an important adrenergic bronchodilator while (R)-denopamine 2, (Fig. 1)2 was
the first orally active and long acting positive inotropic agent. Amino alcohols3 in general have also
found widespread use in modern organic synthesis as chiral inducers. These two aspects have made them
important synthetic targets and various asymmetric syntheses have been reported.4
In connection with our work on the total synthesis of cyclopeptide alkaloids,5 both antipodes of
optically active 2-amino-1-(40-fluoro-30-nitro)phenylethanol 3 were required. From the viewpoint of
practical synthesis, enantiomerically pure cyanohydrin appeared to be an attractive precursor as it is
readily available by both chemical6 and enzymatic procedures.7 However, careful analysis of literature
data revealed that electron deficient aromatic aldehydes, such as nitrobenzaldehyde, were generally
poor substrates in terms of enantioselectivity, most probably due to the background reaction and the
configurational lability of the resulting cyanohydrin.8,9 Furthermore, although (R)-oxynitrilase was easily
available and showed low substrate specificity, the corresponding (S)-oxynitrilase was less accessible
Fig. 1.
∗
Corresponding author. Fax: 33-1-69077247; e-mail: zhu@icsn.cnrs-gif.fr
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(97)00610-1

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and exhibited a more narrow substrate tolerance.9 These observations together with our interest in
chemoenzymatic synthesis of chiral building blocks10 prompted us to examine an alternative way, i.e.,
via enzymatic resolution of racemic amino alcohols. Interestingly, while much attention has been paid to
the enzymatic resolution of 2-amino-2-alkylethanol11 (Eq. 1), studies on that of 2-amino-1-arylethanol
(Eq. 2) were relatively rare and to date, lipase has been elucidated as the enzyme of choice for performing
the desired transformation.12 We report herein that HLE (horse liver esterase) is an efficient alternative
biocatalyst for resolving the N,O-diacetyl derivatives of 2-amino-1-arylethanol in the presence of suitable
organic co-solvent.
Racemic amino alcohol 3 and its acyl derivatives 12a and 12b were prepared as shown in Scheme 1.
Reaction of 4-fluoro-3-nitrobenzaldehyde 10 with TMSCN in the presence of a catalytic amount of
anhydrous ZnI213 gave cyanohydrin 11 which was, without purification, chemoselectively reduced to the
corresponding amino alcohol 3 in excellent overall yield. Acylation with acetic anhydride or propionyl
chloride gave 12a and 12b, respectively, ready for resolution studies.
Scheme 1.
In a preliminary experiment, several commercially available lipases, acylases and esterases have been
screened for resolution by stirring racemic 12a or 12b in a biphasic solution (phosphate buffer pH 7.5
and CH2Cl2) at 37°C. Disappointingly (Table 1), no hydrolysis of compound 12a was observed with
lipases such as PPL (porcine pancreas lipase), PCL (pseudomonas cepacia lipase), WGL (wheat germ
lipase), Aspergillus niger and acylase PS Amano. It was interesting to note that PPL had been employed
to resolve efficiently the structurally related amino alcohols (Eqs. 1 and 2) in organic solvent such as
diisopropyl ether, thus efficiently indicating a remarkable solvent effect. Candida cyclindracea lipase
(CCL, entry 7) did promote the hydrolysis, however, only racemic alcohol was obtained under these
conditions. More promising results were obtained with protease from Bacillus licheniformis (entries 8

T. Laïb et al. / Tetrahedron: Asymmetry 9 (1998) 169–178
171
Table 1
Survey of enzyme catalyzed hydrolysis of 12a and 12ba
and 10) and especially with HLE (entries 9, 11) although the ee of alcohol remained moderate under
these conditions.
In searching for an efficient enzymatic process, the organic co-solvent was generally selected based
on its ability to solubilize the substrates and to enhance the reaction rate, its influence on the enantios-
electivity of a given enzyme was frequently overlooked. Following Kilbanov’s observation14 that the
enantioselectivity of an enzymatic process may depend on the reaction medium, the organic co-solvent
effect was next examined in detail on the HLE catalyzed hydrolysis of substrate 12a. As seen in Table 2,
both reaction rate and enzyme enantioselectivity were indeed influenced markedly by the organic co-
solvent. The best result was obtained when HLE mediated hydrolysis was carried out in a phosphate
buffer (pH 7.5) in the presence of acetone (10% volume, entry 6) as an organic co-solvent at 27°C.
Under these conditions, a reasonable reaction rate was observed and (S)-13 together with unreacted
diacetyl derivative (R)-14 were obtained with an ee greater than 90% at 50% conversion (E=55–60,
Scheme 2). Treatment of (S)-13 and (R)-14 in refluxing HCl (6 N) gave the corresponding (S)-3 and
(R)-3 in quantitative yield without loss of enantiomeric excess. The enantiomeric excess of (S)-13, (S)-3
and (R)-14, (R)-3 (90%) was measured by HPLC analysis of the corresponding (S)-lactate15 15 and 16,
respectively (Fig. 2).
The absolute configuration of 13 and 14 was determined by a modified Mosher’s method16 (Fig. 3).
Thus, coupling of (S)-13 with (S)- and (R)-MTPA acids in the presence of DCC and DMAP afforded the
corresponding (S)- and (R)-MTPA ester in excellent yield. Large negative ∆δ (δS−δR) values were found
for all protons on the left side of the MTPA plan, while all but one diastereotopic proton17 on the right
side of the MTPA plane displayed a large positive ∆δ. Therefore, the (S)-configuration was assigned for
alcohol 13. The (R)-configuration was determined for compound 14 following the same procedure.
The generality of the present enzymatic procedure was briefly examined. As shown in Scheme 3,
treatment of N,O-diacetyl-2-amino-1-phenylethanol 17 with HLE under the above-developed conditions
gave (S)-18 and (R)-19 (Scheme 3). Once again, the ees of (S)-18 and (R)-19 (>90% ee) were determined

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Table 2
Solvent effect of HLE catalyzed hydrolysis of 12aa
Scheme 2.
Fig. 2.
by HPLC analysis of their corresponding (S)-lactate 20 and 21, respectively (Fig. 2), while their
configuration was deduced by the modified Mosher’s ester. Comparison of optical rotations of (S)-18
and (R)-19 with literature values12b (cf. experimental section) proved not only the enantiomerical purity
but also the assignment of their absolute configuations.
In summary, HLE has been shown for the first time, to our knowledge, to be an efficient biocatalyst
for the enantioselective hydrolysis of N,O-diacetyl-2-amino-1-arylethanol. The procedure should find
application in the synthesis of other optically pure aminoalcohols.

T. Laïb et al. / Tetrahedron: Asymmetry 9 (1998) 169–178
173
Fig. 3.
Scheme 3.
1. Experimental section
Melting points were determined with a Kofler apparatus and were uncorrected. Infrared (IR) spectra
1
were recorded on a Nicolet-205 spectrometer. H NMR spectra were measured on Brucker AC-200 (200
MHz), Bruker AC-250 (250 MHz), Bruker (300 MHz) and Bruker WM-400 (400 MHz) spectrometers
with tetramethylsilane as an internal standard (δ ppm). Flash chromatography was performed using
Kieselgel 60 (230–400 mesh, E. Merck) and usually employed a stepwise solvent polarity gradient,
correlated with TLC mobility. Solvents and reagents were purified according to standard laboratory tech-
niques. Optical rotations were determined on a Perkin–Elmer automatic polarimeter at room temperature.
Mass spectra were run on AEI MS-50 (EI), AEI MS-9 (CI) and Kratos MS-80 (FAB), respectively. All
reactions requiring anhydrous conditions or an inert atmosphere were conducted under an atmosphere of
Argon.
1.1. (RS)-2-Amino-1-(40-fluoro-30-nitro)phenylethanol 3
To a suspension of anhydrous ZnI2 (2.27 g, 7.1 mmol) in CH2Cl2 were added, successively, TMSCN
(12.3 mL, 92 mmol) and 4-fluoro-3-nitro benzaldehyde (12.0 g, 71.0 mmol) at room temperature. After
being stirred for 1 h, the reaction mixture was diluted by addition of water and extracted with CH2Cl2.
The combined organic extracts were washed with brine, dried (Na2SO4) and evaporated under reduced
1
pressure to give a quantitative yield of cyanohydrin 11: H NMR (CDCl3, 300 MHz): δ 0.18 (s, 9H),
5.50 (s, 1H), 7.40 (dd, J=8.6, 10.0 Hz, 1H), 7.78 (ddd, J=2.3, 4.0, 8.6 Hz, 1H), 8.19 (dd, J=2.3, 6.8
Hz). To a solution of the obtained crude cyanohydrin 11 in anhydrous THF, was introduced BH3–THF
(142 mL, 1 M in THF, 142 mmol) at 0°C. The resulting solution was heated to reflux for 3 h. After
being cooled to 0°C, excess BH3 was transformed into volatile trimethylborate by careful addition of
anhydrous methanol. The volatiles were removed and the residue was redissolved in MeOH followed
by slow addition of concentrated aqueous HCl solution. Evaporation of organic solvent gave a pale
yellow solid which, after washing with ether afforded an analytically pure hydrochloride salt of the title
compound (RS)-3 (15.1 g, 90%): mp 205°C; IR (KBr), ν 3325, 3079, 1623, 1546, 1539, 1258 cm−1;
1H NMR (CD3OD, 250 MHz): δ 3.01 (dd, J=9.2, 12.7 Hz, 1H), 3.22 (dd, J=3.5, 12.7 Hz, 1H), 5.0 (dd,

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T. Laïb et al. / Tetrahedron: Asymmetry 9 (1998) 169–178
J=3.5, 9.2 Hz, 1H), 7.45 (dd, J=8.5, 9.1 Hz, 1H), 7.8 (ddd, J=2.4, 4.3, 8.5 Hz, 1H), 8.18 (dd, J=2.4, 7.1
Hz, 1H); 13C NMR (CD3OD, 62.5 Hz) δ 46.8, 69.2, 119.7 (d, J=21.4 Hz), 124.6, 134.4 (d, J=8.2 Hz),
138.0, 140.0, 156.1 (d, J=264.0 Hz); MS (CI) m/z 201 (M–HCl)+; Anal. Calcd for C8H10N2O3FCl: C,
40.61; H, 4.26; N, 11.84; Found: C, 40.44; H, 4.48, N, 11.67.
1.2. (S)-2-Amino-1-(40-fluoro-30-nitro)phenylethanol 3
A solution of (S)-13 (1.0 g, 4.13 mmol) was refluxed in HCl (6 N, 10 mL) for 3 h. Evaporation of
the volatiles afforded an analytically pure hydrochloride salt of amino alcohol (S)-3 (970 mg, 99%);
[α]D=+39 (MeOH, c 0.3).
1.3. (R)-2-Amino-1-(40-fluoro-30-nitro)phenylethanol 3
Following the same procedure as described for (S)-3, (R)-3 was prepared from (R)-14 in 98.5% yield:
[α]D=−39 (MeOH, c 0.5).
1.4. (RS)-N,O-Diacetyl-2-amino-1-(40 -fluoro-30-nitro)phenylethanol 12a
To a solution of compound 3 (8.10 g, 34.32 mmol) in CH2Cl2 was added, successively, triethylamine
(9.6 mL, 68.0 mmol), acetic anhydride (6.5 mL, 68 mmol) and DMAP (834.0 mg, 6.84 mmol) at
0°C. After being stirred for 4 h at room temperature, the reaction mixture was diluted by addition of
saturated aqueous NH4Cl solution and extracted with CH2Cl2. The combined organic extracts were
washed with brine, dried (Na2SO4) and evaporated under reduced pressure to give the crude product
12a. Recrystallization (EtOAc/heptane) gave pure 12a (5.0 g). The filtrate was evaporated and purified
by flash chromatography (EtOAc) to give another 2.8 g of 12a. The total yield of 12a was 80%: mp
1
85–90°C; IR (CHCl3), ν 1750, 1679, 1546, 1349 cm−1; H NMR (CDCl3, 250 MHz): δ 1.95 (s, 3H),
2.16 (s, 3H), 3.56 (ddd, J=5.9, 7.6, 14.2 Hz, 1H), 3.70 (ddd, J=4.5, 6.3, 14.2 Hz, 1H), 5.85 (dd, J=4.5,
7.6 Hz, 1H), 6.15 (br s, 1H), 7.32 (dd, J=8.6, 10.4 Hz, 1H), 7.66 (ddd, J=2.2, 4.1, 8.6 Hz, 1H), 8.05 (dd,
J=2.2, 7.0 Hz, 1H); 13C NMR (CDCl3, 62.5 Hz) δ 21.0, 23.1, 43.9, 73.0, 118.8 (d, J=21.1 Hz), 124.1 (d,
J=3.5 Hz), 133.9 (d, J=9.5 Hz), 135.2, 155.2 (d, J=271.0 Hz), 170.0, 170.4; MS (CI) m/z 285 (M+H)+;
Anal. Calcd for C12H13N2O5F: C, 50.71; H, 4.61, N; 9.86; Found: C, 50.77; H, 4.81; N, 9.56.
1.5. (RS)-N,O-Dipropionyl-2-amino-1-(40 -fluoro-30-nitro)phenylethanol 12b
Using propionyl chloride instead of acetic anhydride, (RS)-12b was prepared in 85% yield following
the procedure described above: mp: 95°C; IR (CHCl3), ν 3456, 1744, 1675, 1625, 1543, 1506, 1350
cm−1; 1H NMR (CDCl3, 250 MHz): δ 1.12 (t, J=7.5 Hz, 3H), 1.16 (t, J=7.5 Hz; 3H), 2.2 (q, J=7.5 Hz,
2H), 2.42 (q, J=7.7 Hz, 2H), 3.58 (ddd, J=5.9, 7.7, 14.1 Hz, 1H), 3.7 (ddd, J=4.4, 6.3, 14.1 Hz, 1H), 5.82
(br s, 1H, NH), 5.88 (dd, J=4.4, 7.7 Hz, 1H), 7.3 (dd, J=8.6, 10.4 Hz, 1H), 7.66 (ddd, J=2.3, 4.2, 8.6 Hz,
1H), 8.05 (dd, J=2.3, 7.7 Hz, 1H); 13C NMR (CDCl3, 50.2 MHz) δ 9.1, 9.8, 27.6, 29.7, 44.0, 72.9, 118.9
(d, J=20.3 Hz), 124.0, 138.8 (d, J=8.5 Hz), 133.8, 134.4, 155.3 (d, J=267 Hz), 173.6, 174.0; MS (EI) m/z
313 (M+H)+.

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175
1.6. (RS)-N,O-Diacetyl-2-amino-1-phenylethanol 17
Following the same procedure as described for 12a, compound (RS)-17 was prepared in 75% yield: IR
(CHCl3), ν 1743, 1672, 1525, 1370, 1229 cm−1; 1H NMR (CDCl3, 200 MHz): δ 2.01 (s, 3H), 2.10 (s,
3H), 3.60 (ddd, J=5.7, 7.9, 14.2 Hz, 1H), 3.72 (ddd, J=4.7, 6.1, 14.2 Hz, 1H), 5.7 (br s, 1H), 5.84 (dd,
J=4.7, 7.9 Hz, 1H), 7.3–7.4 (m, 5H); 13C NMR (CDCl3, 50.2 Hz) δ 21.2, 23.2, 44.4, 74.6, 126.4, 128.4,
128.7, 137.7, 170.3, 170.4; MS (CI) m/z 221 (M+H)+.
1.7. (RS)-2-Acetylamino-1-(40-fluoro-3-nitro)phenylethanol 13
To a solution of compound 3 (210 mg, 0.84 mmol) in a mixed solvent CH2Cl2 and water (1/1)
was added, successively, NaOH (68 mg, 1.7 mmol), and acetic anhydride (88 µL, 0.93 mmol). After
being stirred for 3 h at room temperature, the reaction mixture was diluted by addition of saturated
aqueous NH4Cl solution and extracted with CH2Cl2. The combined organic extracts were washed with
brine, dried (Na2SO4) and evaporated under reduced pressure. Recrystallization of the crude product
(EtOAc/heptane) gave pure (RS)-13 (152 mg, 75%): mp 100°C; IR (CHCl3), ν 3355, 1660, 1628, 1598,
1538 cm−1; 1H NMR (CDCl3, 300 MHz): δ 2.05 (s, 3H), 3.37 (ddd, J=5.5, 7.3, 14.4 Hz, 1H), 3.65 (ddd,
J=2.8, 6.4, 14.4 Hz, 1H), 4.30 (s, 1H, OH), 4.98 (dd, J=2.8, 7.3 Hz, 1H), 7.30 (dd, J=8.6, 10.5 Hz, 1H),
7.71 (ddd, J=2.2, 4.1, 8.6 Hz, 1H), 8.10 (dd, J=2.2, 7.1 Hz, 1H); 13C NMR (CDCl3, 62.5 Hz) δ 23.1,
47.8, 72.4, 118.5 (d, J=21.0 Hz), 123.5, 133.1 (d, J=9.1 Hz), 154.8 (d, J=271.0 Hz), 172.5; MS (EI) m/z
243 (M+H)+; Anal. Calcd for C10H11N2O4F: C, 49.59; H, 4.57; N, 11.56; Found: C, 49.42; H, 4.48; N,
11.83.
1.8. (RS)-2-Acetylamino-1-phenylethanol 18
Compound (RS)-18 was prepared as described for (RS)-13. IR (CHCl3), ν 3381, 1665, 1518, 1459,
1419 cm−1; 1H NMR (CDCl3, 300 MHz): δ 1.96 (s, 3H), 3.30 (ddd, J=4.8, 7.9, 13.9 Hz, 1H), 3.64 (ddd,
J=3.4, 7.0, 13.9 Hz, 1H), 3.84 (s, 1H, OH), 4.80 (m, 1H), 6.30 (s, 1H, NH), 7.1–7.3 (m, 5H); 13C NMR
(CDCl3, 62.5 Hz) δ 23.2, 47.6, 73.6, 126.0, 128.0, 141.8, 171.8; MS (EI) m/z 179 (M)+; Anal. Calcd for
C10H13NO2: C, 67.02; H, 7.31; N, 7.81; Found: C, 66.97; H, 7.41; N, 7.53.
1.9. Enzymatic resolution of (RS)-12a
To a solution of racemic (RS)-12a (7.7 g, 27.1 mmol) in mixed solvent (phosphate buffer and acetone
(10/1, total volume 1 L) was added HLE (4.0 g). The reaction mixture was vigorously stirred at 27°C
and the reaction course was monitored by HPLC (hypersil, 5 µm, ODS, 0.4×250 mm; eluant: 35%
CH3CN in H2O, containing 0.01% of TFA). The reaction was stopped at the 50% hydrolysis point (12
h) by addition of methanol and then filtered. After removal of volatiles from the filtrate, the residue
was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4) and
evaporated under reduced pressure. Recrystallization of the crude product (CH2Cl2/heptane) gave pure
(S)-13 (2.3 g). The filtrate was evaporated and purified by flash chromatography (EtOAc/heptane=9/1,
then EtOAc, EtOAc/MeOH=9/1) gave another 0.7 g of (S)-13 (total 3.0 g, 45.7%) and unhydrolyzed ester
(R)-14 (3.4 g, 44.2%). (S)-13 [α]D=+21 (acetone, c 0.2); (R)-14 [α]D=−32 (CHCl3, c 0.9).

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1.10. Enzymatic resolution of (RS)-17
The same procedure applied to (RS)-17 gave (S)-18 and (R)-19. (S)-18: [αD]=+73 {CHCl3, c 0.2;
lit.12b: the (R)-enantiomer: [α]D=−79, (CHCl3, c 0.3)}; (R)-19: [α]D=−55 {(CHCl3, c 0.5; lit.12b: the
(S)-enantiomer: [α]D=+60, (CHCl3, c 0.27)}.
1.11. 2 (2S)-Acetoxypropionic acid 2-acetylamino-1 (1S)-(4-fluoro-3-nitrophenyl)-ethyl ester 15a
To a solution of (S)-13 (30 mg, 0.124 mmol) in CH2Cl2 were added triethylamine (35 µl, 0.248
mmol), (S)-2-acetoxypropionyl chloride (31.4 µl, 0.248 mmol) and a catalytic amount of DMAP (3
mg). After being stirred at room temperature for 1 h, the reaction mixture was diluted by addition of
saturated aqueous NH4Cl solution and extracted with CH2Cl2. The combined organic extracts were
washed with brine, dried (Na2SO4) and evaporated under reduced pressure. Purification by preparative
TLC (EtOAc/acetone=9/1) afforded 15a (34 mg, 80%): [α]D=+21 (CHCl3, c 0.45); IR (CHCl3), ν 1743,
1679, 1546, 1384, 1342, 1272, 1236 cm−1; 1H NMR (CDCl3, 300 MHz): δ 1.52 (d, J=7.2 Hz, 3H), 1.98
(s, 3H), 2.18 (s, 3H), 3.44 (ddd, J=5.5, 8.5, 14.2 Hz, 1H), 3.80 (ddd, J=3.5, 6.8, 14.2 Hz, 1H), 5.04 (q,
J=7.1 Hz, 1H), 5.96 (dd, J=3.5, 8.5 Hz, 1H), 5.97 (br s, 1H), 7.32 (dd, J=8.7, 10.3 Hz, 1H), 7.64 (ddd,
J=2.3, 4.0, 8.6 Hz, 1H), 8.05 (dd, J=2.3, 7.0 Hz, 1H); MS (EI) m/z 357 (M+H)+.
1.12. 2 (2S)-Acetoxypropionic acid 2-acetylamino-1 (1R)-(4-fluoro-3-nitrophenyl)-ethyl ester 16a
[α]D=−86 (CHCl3, c 0.9); IR (CHCl3), ν 1757, 1736, 1680, 1623, 1546, 1370, 1349, 1251 cm−1; 1H
NMR (CDCl3, 300 MHz): δ 1.50 (d, J=7.0 Hz, 3H), 1.98 (s, 3H), 2.16 (s, 3H), 3.35 (ddd, J=4.6, 9.1,
14.2 Hz, 1H), 3.94 (ddd, J=3.2, 7.6, 14.2 Hz, 1H), 4.95 (q, J=7.0 Hz, 1H), 6.04 (dd, J=3.2, 9.1 Hz, 1H),
6.18 (br s, 1H), 7.32 (dd, J=8.6, 10.3 Hz, 1H), 7.64 (ddd, J=2.2, 4.1, 8.6 Hz, 1H), 8.07 (dd, J=2.2, 6.8
Hz, 1H); MS (EI) m/z 357 (M+H)+.
1.13. 2 (2S)-Acetoxypropionic acid 2-[2(2S)-acetoxypropionylamino)]-1 (1S)-(4-fluoro-3-nitrophenyl)-
ethyl ester 15b
[α]D=+7.3 (CHCl3, c 0.8); IR (CHCl3), ν 1746, 1680, 1543, 1374, 1347, 1232, 1095 cm−1; 1H NMR
(CDCl3, 300 MHz) δ 1.45 (d, J=6.8 Hz, 3H), 1.53 (d, J=7.1 Hz, 3H), 2.15 (s, 3H), 2.16 (s, 3H), 3.42
(ddd, J=5.4, 8.7, 14.3 Hz, 1H), 3.85 (ddd, J=3.3, 7.0, 14.3 Hz, 1H), 5.11 (q, J=7.1 Hz, 1H), 5.18 (q,
J=6.8 Hz, 1H), 6.00 (dd, J=3.3, 8.7 Hz, 1H), 6.60 (m, 1H), 7.33 (dd, J=8.7, 10.4 Hz, 1H), 7.64 (ddd,
J=2.3, 4.0, 8.7 Hz, 1H), 8.06 (dd, J=2.3, 6.8 Hz, 1H), MS (EI) m/z 429 (M+H+).
1.14. 2 (2S)-Acetoxypropionic acid 2-[2(2S)-acetoxypropionylamino)]-1 (1R)-(4-fluoro-3-nitrophenyl)-
ethyl ester 16b
[α]D=−59 (CHCl3, c 0.7); IR (CHCl3), ν 1742, 1689, 1543, 1377, 1350, 1244, 1098 cm−1; 1H NMR
(CDCl3, 300 MHz) δ 1.42 (d, J=6.8 Hz, 3H), 1.48 (d, J=7.1 Hz, 3H), 2.13 (s, 6H), 3.52 (ddd, J=5.5, 8.0,
14.0 Hz, 1H), 3.85 (ddd, J=3.3, 6.8, 14.4 Hz, 1H), 4.95 (q, J=7.1 Hz, 1H), 5.12 (q, J=6.8 Hz, 1H), 6.00
(dd, J=3.3, 8.0 Hz, 1H), 5.60 (m, 1H), 7.31 (dd, J=8.7, 10.3 Hz, 1H), 7.64 (ddd, J=2.3, 4.1, 8.7 Hz, 1H),
8.06 (dd, J=2.3, 6.9 Hz, 1H), MS (EI) m/z 429 (M+H+).

T. Laïb et al. / Tetrahedron: Asymmetry 9 (1998) 169–178
177
1.15. 2 (2S)-Acetoxypropionic acid 2-acetylamino-1 (1S)-phenyl ethyl ester 20
1
[α]D=+28 (CHCl3, c 0.25); IR (CHCl3), ν 1743, 1675, 1525, 1375, 1268 cm−1; H NMR (CDCl3,
300 MHz): δ 1.52 (d, J=7.0 Hz, 3H), 2.00 (s, 3H), 2.16 (s, 3H), 3.40 (ddd, J=4.9, 9.3, 14.3 Hz, 1H), 3.82
(ddd, J=3.5, 7.2, 14.3 Hz, 1H), 5.05 (q, J=7.0 Hz, 1H), 5.90 (br s, 1H), 5.96 (dd, J=3.5, 9.3 Hz, 1H), 7.3
(m, 5H); MS (EI) m/z 293 (M)+.
1.16. 2 (2S)-Acetoxypropionic acid 2-acetylamino-1 (1R)-phenyl ethyl ester 21
[α]D=−97 (CHCl3, c 0.3); IR (CHCl3), ν 1743, 1675, 1525, 1375, 1256 cm−1; 1H NMR (CDCl3, 300
MHz): δ 1.50 (d, J=7.0 Hz, 3H), 2.02 (s, 3H), 2.14 (s, 3H), 3.38 (ddd, J=4.1, 9.8, 14.1 Hz, 1H), 3.9 (ddd,
J=3.2, 7.8, 14.1 Hz, 1H), 4.95 (q, J=7.0 Hz, 1H), 6.02 (dd, J=3.2, 9.8 Hz, 1H), 6.12 (br s, 1H), 7.3 (m,
5H,); MS (EI) m/z 293 (M)+.
Acknowledgements
Financial support from the CNRS and a doctoral fellowship from ‘Ligue National Contre le Cancer’
to T. Laïb are gratefully acknowledged.
References
1. Dictionary of Drugs, Elks, J.; Ganellin, C. R. (Eds), Chapman and Hall, 1990, p. 1160.
2. ibid, 358.
3. (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49–69; (b) Ajer, D. J.; Prakash, I.; Schaad, D. R. Chem.
Rev. 1996, 96, 835–875.
4. For some selected examples, see: (a) Elliott, J. D.; Choi, V. M. F.; Johnson, W. S. J. Org. Chem. 1983, 48, 2294–2295;
(b) Yamashita, H. Chem. Lett. 1987, 525–528; (c) Kitamura, M.; Okhuma, T.; Inoue, S.; Sayo, N.; Kumobayashi, H.;
Akutagawa, S.; Ohta, T.; Takaya, H. Noyori, R. J. Am. Chem. Soc. 1988, 110, 629–631; (d) Ziegler, T.; Hörsch, B.;
Effenberger, F. Synthesis 1990, 575–578; (e) Corey, E. J.; Link, J. O. J. Org. Chem. 1991, 56, 442–444; (f) Reetz, M.
T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531–1546; (g) Oppolzer, W.; Tamura, O.; Sundarababu, G.; Signer, M. J. Am.
Chem. Soc. 1992, 114, 5900–5904; (h) An, B.; Kim, H.; Cha, J. K. J. Org. Chem. 1993, 58, 1273–1275; (i) Kawaguchi, T.;
Saito, K.; Matsuki, K.; Iwakuma, T.; Takeda, M. Chem. Pharm. Bull. Jpn 1994, 41, 639–642; (j) Donohue, A. C.; Jackson,
W. R. Aust. J. Chem. 1995, 48, 1741–1746; (k) Li, G.; Chang, H. T.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996,
35, 451–454; (l) Martinez, L. E.; Leighton, J. L.; Carsten, D. H.; Jacobsen, E. N. J. Am. Chem. Soc. 1996, 118, 7420–7421;
(m) Effenberger, F.; Jäger, J. J. Org. Chem. 1997, 62, 3867–3873 and references cited therein.
5. Zhu, J.; Laib, T.; Chastanet, J.; Beugelmans, R. Angew. Chem., Int. Ed. Engl. 1996, 35, 2517–2519.
6. North, M. Synlett 1993, 807–820.
7. Effenberger, F. Angew. Chem., Int. Ed. Engl. 1994, 33, 1555–1564.
8. (a) Matthews, B. R.; Jackson, W. R.; Jayatilake, G. S.; Wilshire, C.; Jacobs, H. A. Aust. J. Chem. 1988, 41, 1697–1709; (b)
Belokon, Y.; Flego, M.; Ikonnikov, N.; Moscalenko, M.; North, M.; Orizu, C.; Tararov, V.; Tasinazzo, M. J. Chem. Soc.,
Perkin Trans 1 1997, 1293–1295.
9. Faber, K. Biotransformation In Organic Chemistry, Springer–Verlag, 2nd Edn, 1995, pp. 240–243.
10. Vergne, C.; Bois-Choussy, M.; Ouazzani, J.; Beugelmans, R.; Zhu, J. Tetrahedron: Asymmetry 1997, 8, 391–398.
11. (a) Francalanci, F.; Cesti, P.; Cabri, W.; Bianchi, D.; Martinengo, T.; Foa, M. J. Org. Chem. 1987, 52, 5079–5082; (b)
Gotor, V.; Brieva, R.; Rebolledo, F. J. Chem. Soc., Chem. Commun. 1988, 957–958; (c) Bevinakatti, H. S.; Newadkar, R. V.
Tetrahedron: Asymmetry 1990, 1, 583–586; (d) Nieduzak, T. R.; Carr, A. A.; Tetrahedron: Asymmetry 1990, 1, 535–536; (e)
Ader, U.; Schneider, M. P. Tetrahedron: Asymmetry 1992, 3, 205–208; (f) Fernandez, S.; Brieva, R.; Rebolledo, F.; Gotor,
V. J. Chem. Soc., Perkin Trans. 1 1992, 2885–2889; (g) Maestro A.; Astorga, C.; Gotor, V. Tetrahedron: Asymmetry 1997,
8, 3153–3159 and references cited therein.

178
T. Laïb et al. / Tetrahedron: Asymmetry 9 (1998) 169–178
12. (a) Kanerva, L. T.; Rahiala, K.; Vänttinen, E. J. Chem. Soc., Perkin Trans. 1 1992, 1759–1762; (b) Izumi, T.; Fukaya, K.
Bull. Chem. Soc. Jpn 1993, 66, 1216–1221; (c) Lundell, K.; Kanerva, L. T. Tetrahedron: Asymmetry 1995, 6, 2281–2286;
(d) Takayama, S.; Moree, W. J.; Wong, C. H. Tetrahedron Lett. 1996, 37, 6287–6290.
13. Evans, D. A.; Carroll, G. L.; Truesdale, L. K. J. Org. Chem. 1974, 39, 914–917.
14. Kitaguchi, H.; Fitzpatrick, P. A.; Huber, J. E.; Kilbanov, A. M. J. Am. Chem. Soc. 1989, 111, 3094–3095; (b) Sakurai, T.;
Margolin, A. L.; Russel, A. J.; Kilbanov, A. M. J. Am. Chem. Soc. 1988, 110, 7236–7237.
15. Zhu, J.; Beugelmans, R.; Bourdet, S.; Chastanet, J.; Roussi, G. J. Org. Chem. 1995, 60, 6389–6396.
16. (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519; (b) Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J.
Org. Chem. 1973, 38, 2143–2147; (c) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092–4096.
17. Steric crowding around the ester moiety may cause the irregularity, see: (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa,
H. J. Org. Chem. 1991, 56, 1296–1298; (b) Kusumi, T.; Fujita, Y.; Ohtani, I.; Kakisawa, H. Tetrahedron Lett. 1991, 32,
2923–2926. However, in our case, steric hinderance is not obvious. We think that the possible intramolecular hydrogen
bond between the amide proton and the ester carbonyl function may modify the MTPA plane and cause this observed
irregularity.