Enzymatic resolution of (±)-2-(N(β)-t-butoxycarbonyl-N(α)- methylhydrazino)cycloalkanols

Article abstract of DOI:10.1016/S0957-4166(99)00535-2

Racemates of cis- and trans-2-(N(β)-t-butoxycarbonyl-N(α)- methylhydrazino)cyclopentanols and -cyclohexanols 1-4 were resolved through lipase PS- or Novozym 435-catalysed asymmetric acylation of the secondary OH group at the (R)-stereogenic centre. High e

Full text of DOI:10.1016/S0957-4166(99)00535-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4619–4626
Enzymatic resolution of (±)-2-(Nβ-t-butoxycarbonyl-
Nα-methylhydrazino)cycloalkanols
Eniko˝ Forró, Zsolt Szakonyi and Ferenc Fülöp ∗
Institute of Pharmaceutical Chemistry,† Albert Szent-Györgyi Medical University, H-6701, Szeged, POB 121, Hungary
Received 8 November 1999; accepted 23 November 1999
Abstract
Racemates of cis- and trans-2-(Nβ-t-butoxycarbonyl-Nα-methylhydrazino)cyclopentanols and -cyclohexanols
1–4 were resolved through lipase PS- or Novozym 435-catalysed asymmetric acylation of the secondary OH group
at the (R)-stereogenic centre. High enantioselectivity (E >200) was observed when vinyl acetate or vinyl butyrate
was used in diisopropyl ether, resulting in the enantiopure hydrazino esters 1a–4a and hydrazino alcohols 1b–4b.
Methanolysis of the esters 1a–4a afforded the corresponding 2-hydrazinocycloalkanols 1c–4c (ee usually >95%).
© 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Many 1,2- and 1,3-aminoalcohols and their derivatives are known to be useful building blocks for
the synthesis of various pharmaceutically important compounds.1–5 We have recently described the
enzymatic resolution of several 2-substituted cycloalkanols,6–8 e.g. aminoalcohols or aminoalcohol
precursors. Chiral hydrazinoalcohols derived from 1,2-aminoalcohols are also important synthons in
enantioselective syntheses, e.g. the reactions of various aromatic aldehydes with chiral hydrazine pre-
pared from (R)-(−)-2-aminobutanol were reported by Bataille et al.: the enantioselective addition of
organometals to chiral hydrazones, followed by catalytic hydrogenolysis, afforded the corresponding
chiral α-phenylalkanamines.9,10
The primary focus of this work was to find the optimum conditions for the enzymatic resolution
of cis- and trans-2-(Nβ-t-butoxycarbonyl-Nα-methylhydrazino)cycloalkanols by using lipase-catalysed
acylation (Scheme 1). To the best of our knowledge, the enzymatic resolution of hydrazino alcohols has
not been described previously.
∗
†
Corresponding author. Tel: 36 62 545 564; fax: 36 62 420 604; e-mail: fulop@pharma.szote.u-szeged.hu
From 1 January 2000, Institute of Pharmaceutical Chemistry, University of Szeged.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00535-2
tetasy 3170

4620
E. Forró et al. / Tetrahedron: Asymmetry 10 (1999) 4619–4626
Scheme 1.
2. Results and discussion
Lipase PS (Pseudomonas cepacia) and Novozym 435 (lipase from Candida antarctica B) are the most
commonly used enzymes for the resolution of secondary alcohols.6–8,11–13 Extensive lipase screening
for compound 2 in diisopropyl ether indicated that, besides lipase PS and Novozym 435, lipase AK
(Pseudomonas fluorescens) is also a promising catalyst for acetylation (Table 1). On the basis of previous
experience with lipase PS and Novozym 435 catalysis,6–8 diisopropyl ether was used as solvent and vinyl
acetate as irreversible acyl transfer reagent throughout the work (vinyl alcohol undergoes irreversible
tautomerisation to acetaldehyde). Lipase AY does not exhibit any selectivity in the acetylation of 2,
yielding nearly racemic products, and porcine pancreatic lipase (PPL) even catalysed the acetylation
selectively, the reaction rate being very slow (Table 1). The acetylation of 1 catalysed by lipase PS,
Novozym 435 and lipase AK displayed a similarly high enantioselectivity (enantiomeric ratio E >200)14
as in the case of 2 (Table 1). Because of certain technical peak-separation problems in the chromatograms
in the case of 1 (the acetate and possible underivatised alcohol peaks partially overlap), the acylation of 1
with vinyl butyrate was also investigated. The lipase PS- and lipase AK-catalysed butyrylation reactions
of 1 (Table 1, rows 4 and 10) proceeded more rapidly than the acetylations, while, surprisingly, a slower
reaction was observed in the Novozym 435-catalysed butyrylation of 1 (row 7).
Although the enzymatic reactions can also be controlled via the amount of enzyme,7,8 the effect is less
pronounced in the case of the lipase PS-catalysed acetylation of 1 (Table 1, rows 2 and 3).
Gram-scale preparations of the enantiomers of 1–4 were performed in diisopropyl ether with lipase PS
or Novozym 435 as catalyst and vinyl acetate or vinyl butyrate as acyl donor. The results are reported in
Table 2 and in the Experimental section.
It is important to note that, in good agreement with our previous observation,8 the size of the
cycloalkane ring had a clear effect on the rate of enantioselective acylation: the acetylation of the
five-membered aminoalcohols (1 and 2) proceeded more rapidly than that of the six-membered ones
(3 and 4). Some doubts arose about the possibilities for the resolution of cis-2-(Nβ-t-butoxycarbonyl-Nα-
methylhydrazino)cyclohexanol 3 because of the rather long reaction time needed to reach the theoretical
50% conversion, due to the probable steric hindrance; in spite of the long reaction time, the products
were characterised by an excellent enantiomeric excess (Table 2, row 5) at 50% conversion.
The esters 1a–4a produced by the (R)-selective acetylation of the cyclopentanols and cyclohexanols
were alcoholised15 to the corresponding alcohols 1c–4c in K2CO3/MeOH, at room temperature, without
loss of enantiopurity (Scheme 2).
2.1. Absolute configurations
The analysed chromatograms indicated that the corresponding enantiomers of 1–4 reacted preferen-
tially on lipase PS or Novozym 435 catalysis, in accordance with the Kazlauskas model for the active site

E. Forró et al. / Tetrahedron: Asymmetry 10 (1999) 4619–4626
4621
Table 1
Lipase-catalysed (i: 30 mg ml−1, ii: 50 mg ml−1) acylation of 1 and 2 (0.1 M) with vinyl acetate (VA)
or vinyl butyrate (VB, 0.2 M) in diisopropyl ether, at 25°C
Table 2
Enzyme-catalysed resolution of 1–4 in the presence of Novozym 435 (30 mg ml−1) or lipase PSa (50
mg ml−1) and vinyl acetate (VA, 0.2 M) or vinyl butyrate (VB, 0.2–0.4 M) in diisopropyl ether, at
25°C
of lipases (a lipase distinguishes the two enantiomers on the basis of the sizes of the substituents Rlarge
and Rsmall at the alcoholic stereocentre [RsmallCH(OH)Rlarge]: the more reactive enantiomer involves the
(R) absolute configuration when the Cahn–Ingold–Prelog priority of group Rlarge is higher than that of
group Rsmall and H is behind the plane).16,17 The validity of this was proved in the case of trans-2-(Nβ-t-

4622
E. Forró et al. / Tetrahedron: Asymmetry 10 (1999) 4619–4626
Scheme 2.
butoxycarbonyl-Nα-methylhydrazino)cyclohexanol 4. For this purpose, the enantiomer 4b was reduced
20
catalytically to the corresponding trans-2-methylaminocyclohexanol hydrochloride. The value of [α]
D
+34.0 (c 0.2, H2O; ee 91%) for the reduced product and the literature value for the (1R,2R)-trans-2-
20
D
methylaminocyclohexanol hydrochloride18 ([α] −56 (c 1, H2O)) indicate the (R) selectivity for the
enzymatic acylation. Therefore, the (1R,2S) configuration is established for the esters of cis cyclanols
(1a and 3a), and the (1R,2R) configuration for the trans (2a and 4a) counterparts.
3. Experimental
3.1. Materials and methods
The racemic trans-2-methylaminocyclopentanol and -cyclohexanol 6 were prepared from the cor-
responding epoxides 5 by methylamine ring opening.19 The trans aminoalcohols 6 were inverted to
the racemic cis counterparts by acetylation, followed by thionyl chloride oxazolidine formation and
hydrolysis (Scheme 3), as described earlier.20
Scheme 3. (i) NH2Me; (ii) Ac2O, SOCl2; (iii) NaOH; (iv) NaNO2, AcOH, H2O, 0–5°C; (v) LiAlH4, THF; (vi) Boc2O, rt
Vinyl acetate was purchased from Aldrich Co., and vinyl butyrate from Fluka. Lipase PS and lipase
AK were obtained from Amano Pharmaceuticals, and Novozym 435 as an immobilised preparation from
Novo Nordisk. Before use, lipase PS (5 g) was dissolved in Tris–HCl buffer (0.02 M; pH 7.8) in the
presence of sucrose (3 g), followed by adsorption on Celite (17 g) (Sigma). The lipase preparation thus
obtained contained 20% (w/w) of lipase.

E. Forró et al. / Tetrahedron: Asymmetry 10 (1999) 4619–4626
4623
3.2. General method for preparation of the racemic cis- and trans-2-(Nβ-t-butoxycarbonyl-Nα-methyl-
hydrazino)cyclopentanols (1 and 2) and -cyclohexanols (3 and 4)
To a stirred solution of the hydrochloride salt of 6 or 7 (33.8 mmol) in 20 ml of water were added
dropwise NaNO2 (4.35 g, 63 mmol), dissolved in 5 ml of water, and acetic acid (2.94 g, 49 mmol) at
0°C. The mixture was stirred for 5 h at 0–5°C, and was then extracted with ethyl acetate (3×50 ml). The
organic phase was washed with saturated NaHCO3 solution, dried (Na2SO4), filtered and evaporated to
dryness. The resulting oil was dissolved in 20 ml of dry THF and was added dropwise to a stirred mixture
of LiAlH4 (3.65 g, 96 mmol) and dry THF (80 ml) at 0°C. After stirring and refluxing for 1.5 h (the end
of the reduction was detected by means of TLC), the mixture was decomposed with 7 ml of water under
ice cooling. The inorganic material was filtered off and washed with THF. After drying and evaporation,
the pale-yellow oily hydrazino alcohol was obtained. To the solution of the crude hydrazino alcohol in
40 ml of dioxane, 20 ml of water and 20 ml of a 1 M NaOH solution of di-t-butyl dicarbonate (4.8 g,
22 mmol) dissolved in 10 ml of 1,4-dioxane were added dropwise at 0°C. The solution was stirred for 4
h at room temperature, the dioxane was evaporated off and the aqueous solution was acidified (pH=2.5)
by treatment with 10% sulphuric acid solution. The solution was extracted with ethyl acetate (3×50
ml), and the organic phase was dried (Na2SO4), filtered and evaporated to dryness. The resulting yellow
crystalline product was recrystallised from diisopropyl ether.
Compound (±)-1 (yield: 35%): 1H NMR (400 MHz, CDCl3) δ (ppm): 1.46 (9H, s, 3×CH3), 1.62–1.96
(6H, m, 3×CH2), 2.62 (3H, s, CH3), 2.68 [1H, m, CHN(Me)(NHBoc)], 3.9–4.0 (1H, b s, NH), 4.01 (1H,
m, CHOH), 5.57 (1H, b s, OH); anal. calcd for C11H22N2O3: C, 57.37; H, 9.63; N, 12.16; found: C,
57.54; H, 9.13; N, 12.43; mp: 111–113°C.
1
Compound (±)-2 (yield: 39%): H NMR (400 MHz, CDCl3) δ (ppm): 1.39–1.98 (6H, m, 3×CH2),
1.46 (9H, s, 3×CH3), 2.61 (3H, s, CH3), 2.88 [1H, dd, J=14.6, 7.0 Hz, CHN(Me)(NHBoc)], 3.0 (1H, b s,
NH), 3.89 (1H, dd, J=14.2, 6.9 Hz, CHOH), 5.48 (1H, b s, OH); anal. calcd for C11H22N2O3: C, 57.37;
H, 9.63; N, 12.16; found: C, 57.54; H, 9.48; N, 12.27; mp: 149–151°C.
1
Compound (±)-3 (yield: 32%): H NMR (400 MHz, CDCl3) δ (ppm): 1.10–2.40 (8H, m, 4×CH2),
1.46 (9H, s, 3×CH3), 2.61 (3H, s, CH3), 2.61 [1H, m, CHN(Me)(NHBoc)], 3.97 (1H, m, CHOH), 5.45
(1H, b s, OH); anal. calcd for C12H24N2O3: C, 58.99; H, 9.90; N, 11.47; found: C, 58.76; H, 9.63; N,
11.75; mp: 122–123°C.
Compound (±)-4 (yield: 41%): 1H NMR (400 MHz, CDCl3) δ (ppm): 1.20–2.40 (9H, m, 4×CH2 and
remaining CH), 1.46 (9H, s, 3×CH3), 2.62 (3H, s, CH3), 3.25 (1H, m, CHOH), 4.65 (1H, b s, NH), 5.35
(1H, b s, OH); anal. calcd for C12H24N2O3: C, 58.99; H, 9.90; N, 11.47; found: C, 58.39; H, 9.66; N,
11.77; mp: 135–137°C.
3.3. General procedure for a typical small-scale experiment
The 2-(Nβ-t-butoxycarbonyl-Nα-methylhydrazino)cycloalkanol 1–4 (0.1 M solution) in an organic
solvent (3 ml) was added to lipase PS (50 mg ml−1) or Novozym 435 (30 mg ml−1). A vinyl ester
(0.2 M in the reaction mixture) was added. The mixture was shaken at 25°C. The progress of the reaction
was followed by taking samples (0.1 ml) from the reaction mixture at intervals and analysing them by
gas chromatography. The unreacted alcohol in the sample was derivatised with propionic anhydride in
the presence of 4-dimethylaminopyridine and pyridine before the gas chromatographic analysis. The ee
values of the unreacted alcohol (1b–4b) and the produced ester enantiomers (1a–4a) were determined by
gas chromatography on a Chrompack CP-Chirasil-DEX CB column (25 m).

4624
E. Forró et al. / Tetrahedron: Asymmetry 10 (1999) 4619–4626
3.4. Gram-scale resolution of (±)-cis-2-(Nβ-t-butoxycarbonyl-Nα-methylhydrazino)cyclopentanol 1
Following the procedure described above, racemic 1 (0.5 g, 2.2 mmol) and vinyl butyrate (0.36
ml, 4.4 mmol) in diisopropyl ether (30 ml) were added to lipase PS (1.5 g, 50 mg ml−1); this
20
afforded the unreacted (1S,2R)-1b (0.13 g, 0.58 mmol; [α] −20.5 (c 0.5, MeOH); mp 117–118°C;
D
20
D
ee 99%) and the ester (1R,2S)-1a (0.31 g oil, 1.03 mmol; [α] −28.5 (c 0.5, MeOH); ee 99%) in
23 h. Within 3–4 h, on stirring in K2CO3/methanol at room temperature, the ester enantiomer 1a
20
D
underwent quantitative deacylation, resulting in the corresponding alcohol (1R,2S)-1c ([α] +20.2 (c
0.5, MeOH); mp 117–118°C; ee 99%); 1H NMR (400 MHz, CDCl3) δ (ppm) for 1a: 0.95 (3H, t, CH3),
0.95–1.85 (6H, m, 3×CH2), 1.44 (9H, s, 3×CH3), 2.3 (4H, m 2×CH2), 2.71 (3H, s, CH3), 3.5 [1H, m,
CHN(Me)(NHBoc)], 5.20 (1H, m, CHOCOPr), 6.7 (1H, b s, NH); anal. calcd for C15H28N2O4: C, 59.98;
H, 9.40; N, 9.33; found: C, 59.81; H, 9.20; N, 9.66.
1H NMR (400 MHz, CDCl3) δ (ppm) data for 1b and 1c are similar to those for (±)-1; anal. calcd for
C11H22N2O3: C, 57.37; H, 9.63; N, 12.16; found for 1b: C, 57.17; H, 9.60; N, 12.11; found for 1c: C,
57.51; H, 9.58; N, 12.09.
3.5. Gram-scale resolution of (±)-trans-2-(Nβ-t-butoxycarbonyl-Nα-methylhydrazino)cyclopentanol 2
Following the procedure described above, the reaction of racemic 2 (0.38 g, 1.65 mmol) and vinyl
acetate (0.20 ml, 3.3 mmol) in diisopropyl ether (50 ml) in the presence of Novozym 435 (1.5 g, 30 mg
ml−1) afforded the unreacted (1S,2S)-2b (0.12 g oil, 0.52 mmol; [α]20 +30.2 (c 0.5, MeOH); ee 99%) and
D
20
D
the ester (1R,2R)-2a (0.19 g oil, 0.70 mmol; [α] −49.5 (c 0.5, MeOH); ee 91.3%) in 7 h. Within 3−4
h, on stirring in K2CO3/methanol at room temperature, the ester enantiomer 2a underwent quantitative
20
D
deacylation, resulting in the corresponding alcohol (1R,2R)-2c ([α] −28.4 (c 0.68, MeOH); mp
1
149–151°C; ee 94.5%); H NMR (400 MHz, CDCl3) δ (ppm) for 2a: 1.44 (9H, s, 3×CH3), 1.55–2.0
(6H, m, 3×CH2), 2.0 (3H, s, CH3), 2.6 (3H, s, CH3), 3.18 [1H, m, CHN(Me)(NHBoc)], 5.1 (1H, m,
CHOCOCH3), 5.65 (1H, b s, NH); anal. calcd for C13H24N2O4: C, 57.33; H, 8.88; N, 10.29; found: C,
58.01; H, 9.13; N, 10.59).
1H NMR (400 MHz, CDCl3) δ (ppm) data for 2b and 2c are similar to those for (±)-2; anal. calcd for
C11H22N2O3: C, 57.37; H, 9.63; N, 12.16; found for 2b: C, 57.11; H, 9.33; N, 12.24; found for 2c: C,
56.97; H, 9.51; N, 12.15.
3.6. Gram-scale resolution of (±)-cis-2-(Nβ-t-butoxycarbonyl-Nα-methylhydrazino)cyclohexanol 3
Following the procedure described above, the reaction of racemic 3 (0.5 g, 2.03 mmol) and vinyl
acetate (0.49 ml, 8.1 mmol) in diisopropyl ether (40 ml), in the presence of lipase PS (2.0 g, 50 mg ml−1),
20
afforded the unreacted (1S,2R)-3b (0.25 g, 1.02 mmol; [α] −3.4 (c 0.53, MeOH); mp 125–126°C; ee
D
20
97.9%) and the ester (1R,2S)-3a (0.23 g oil, 0.81 mmol; [α] −31.5 (c 0.55, MeOH); ee >99%) in 335
D
h. Within 3–4 h, on stirring in K2CO3/methanol at room temperature, the ester enantiomer 3a underwent
quantitative deacylation, resulting in the corresponding alcohol (1R,2S)-3c ([α]20 +3.8 (c 0.53, MeOH);
D
1
mp 123–125°C; ee >99%). H NMR (400 MHz, CDCl3) δ (ppm) for 3a: 1.25–1.96 (8H, m, 4×CH2),
1.44 (9H, s, 3×CH3), 2.09 (3H, s, CH3), 2.64 (3H, s, CH3), 2.81 [1H, m, CHN(Me)(NHBoc)], 5.3 (1H,
m, CHOCOCH3), 5.95 (1H, b s, NH); anal. calcd for C14H26N2O4: C, 58.72; H, 9.15; N, 9.78; found: C,
58.87; H, 9.09; N, 9.77.

E. Forró et al. / Tetrahedron: Asymmetry 10 (1999) 4619–4626
4625
1H NMR (400 MHz, CDCl3) δ (ppm) data for 3b and 3c are similar to those for (±)-3; anal. calcd for
C12H24N2O3: C, 58.99; H, 9.90; N, 11.47; found for 3b: C, 59.02; H, 9.60; N, 11.40; found for 3c: C,
59.10; H, 9.81; N, 11.19.
3.7. Gram-scale resolution of (±)-trans-2-(Nβ-t-butoxycarbonyl-Nα-methylhydrazino)cyclohexanol 4
Following the procedure described above, racemic 4 (1.5 g, 6.1 mmol) and vinyl acetate (0.74 ml,
12.2 mmol) in diisopropyl ether (70 ml), in the presence of Novozym 435 (2.1 g, 30 mg ml−1), afforded
20
the unreacted (1S,2S)-4b (0.31 g, 1.26 mmol; [α] +34.0 (c 0.5, MeOH); mp 131–132°C; ee 98.6%)
D
20
D
and the ester (1R,2R)-4a (0.34 g oil, 1.19 mmol; [α] −40.5 (c 0.5, MeOH); ee 98.9%) in 168 h.
Within 3–4 h, on stirring in K2CO3/methanol at room temperature, the ester enantiomer 4a underwent
20
quantitative deacylation, resulting in the corresponding alcohol (1R,2R)-4c ([α] −31.5 (c 0.5, MeOH);
D
1
mp 128–129°C; ee 95.9%). H NMR (400 MHz, CDCl3) δ (ppm) for 4a: 1.2–2.0 (8H, m, 4×CH2),
1.44 (9H, s, 3×CH3), 2.0 (3H, s, CH3), 2.6 (3H, s, CH3), 2.7 [1H, m, CHN(Me)(NHBoc)], 4.8 (1H, m,
CHOCOCH3), 5.8 (1H, b s, NH); anal. calcd for C14H26N2O4: C, 58.72; H, 9.15; N, 9.78; found: C,
59.03; H, 8.89; N, 9.55.
1H NMR (400 MHz, CDCl3) δ (ppm) data for 4b and 4c are similar to those for (±)-4; anal. calcd for
C12H24N2O3: C, 58.99; H, 9.90; N, 11.47; found for 4b: C, 59.12; H, 9.81; N, 11.21; found for 4c: C,
58.84; H, 9.82; N, 11.30.
3.8. General method for the methanolysis of 1a–4a to the corresponding alcohol enantiomers 1c–4c
A mixture of 1 mmol of 1a–4a and K2CO3 (0.33 g, 2.4 mmol) in 25 ml of methanol was stirred for
4 h at room temperature.15 After evaporation, the residue was dissolved in 20 ml of water and extracted
with diethyl ether (3×30 ml). The organic phase was dried (Na2SO4), filtered and evaporated to dryness
and the product (1c–4c) was recrystallised from diisopropyl ether.
3.9. Transformation of 4b to (+)-(1S,2S)-2-methylaminocyclohexanol hydrochloride (+)-6·HCl (n=2)
To a solution of 4b (0.10 g) in 1 ml of CH2Cl2, TFA (5 ml) was added at room temperature.15 After
stirring for 25 min at room temperature, 150 ml of ice-cooled water was added and the mixture was
extracted with diethyl ether (2×30 ml). The water phase was basified (pH=10) and extracted with CHCl3
(4×30 ml), and the combined organic phase was dried (Na2SO4), filtered and evaporated to dryness.
The residual yellow oil was dissolved in 25 ml of methanol and hydrogenolysed in the presence of
0.05 g of Raney-Ni catalyst under hydrogen (1 bar) in an ultrasonic bath at room temperature for
2 h.21 After filtration and evaporation, the hydrochloride salt was prepared with ethanol containing
22% of dry hydrogen chloride. The product was transferred together with racemic (±)-6·HCl (n=2;
in the presence of 4-dimethylaminopyridine and pyridine) to a chiral column and accepted as one
20
enantiomer of the racemic (±)-6. Since the sign of rotation of our synthetic product ([α] +34.0 (c
D
20
D
0.2, H2O; ee 91%)) is opposite to that of the literature ([α] −56 (c 1, H2O) for (1R,2R)-trans-2-
methylaminocyclohexanol hydrochloride18), its absolute stereochemistry can be assigned as (+)-(1S,2S)-
2-methylaminocyclohexanol hydrochloride.

4626
E. Forró et al. / Tetrahedron: Asymmetry 10 (1999) 4619–4626
Acknowledgements
The authors’ thanks are due to OTKA (grant no. T 030452) and MKM (grant no. FKFP 0535/1999)
for financial support.
References
1. Luna, A.; Maestro, A.; Astorga, C.; Gotor, V. Tetrahedron: Asymmetry 1999, 10, 1969.
2. Anrich, H. G.; Soebert, M.; Harms, K. Tetrahedron 1999, 55, 1249.
3. Fülöp, F.; Simon, L.; Simon-Talpas, G.; Bernáth, G. Synth. Commun. 1998, 28, 2303.
4. Fülöp, F.; Bernáth, G.; Pihlaja, K. Adv. Heterocyclic Chem. 1998, 69, 349.
5. Caira, M. R.; Hunter, R.; Nassimbeni, L. R.; Stevens, A. T. Tetrahedron: Asymmetry 1999, 10, 2175.
6. Forró, E.; Lundell, K.; Fülöp, F.; Kanerva, L. T. Tetrahedron: Asymmetry 1997, 8, 3095.
7. Forró, E.; Kanerva, L. T.; Fülöp, F. Tetrahedron: Asymmetry 1998, 9, 513.
8. Forró, E.; Fülöp, F. Tetrahedron: Asymmetry 1999, 10, 1985.
9. Bataille, P.; Paterne, M.; Brown, E. Tetrahedron: Asymmetry 1998, 9, 2181.
10. Bataille, P.; Paterne, M.; Brown, E. Tetrahedron: Asymmetry 1999, 10, 1579.
11. Roberts, S. M. J. Chem. Soc., Perkin Trans. 1 1998, 157.
12. Roberts, S. M. J. Chem. Soc., Perkin Trans. 1 1999, 1.
13. Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolases in Organic Synthesis; Wiley-VCH: Weinheim, 1999; pp. 65–95.
14. Rakels, J. L. L.; Straathof, J. J.; Heijnen, J. J. J. Enzyme Microb. Technol. 1993, 15, 1051.
15. Sakai, N.; Ohfune, Y. J. Am. Chem. Soc. 1992, 114, 998.
16. Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia, L. A. J. Org. Chem. 1991, 56, 2656.
17. Cygler, M.; Grochulski, P.; Kazlauskas, R. J.; Schrag, J. D.; Bouthillier, F.; Rubin, B.; Serreqi, A. N.; Gupta, A. K. J. Am.
Chem. Soc. 1994, 116, 3180.
18. Pracejus, H.; Pracejus, G.; Costisella, B. J. Prakt. Chem. 1987, 329, 235.
19. Hawkins, L. R.; Barmand, R. A. Can. J. Chem. 1958, 36, 220.
20. Schaus, S. E.; Larrow, J. F.; Jacobsen, E. N. J. Org. Chem. 1997, 62, 4197.
21. Enders, D.; Klatt, M.; Funk, R. Synlett 1993, 226.