Vapour-assisted enzymatic hydrolysis of β-lactams in a solvent-free system

Article abstract of DOI:10.1016/j.tetasy.2008.04.003

A new, solvent-free, vapour-assisted method, developed for the synthesis of carbocyclic cis β-amino acid enantiomers through the Candida antarctica lipase B-catalysed enantioselective (E >200) hydrolysis of β-lactams with 0.5 equiv of H₂O at 70 °C, has been demonstrated to be applicable on a preparative scale to produce (±)-2 (the starting racemate for cispentacin), (±)-3 (the starting racemate for 4-tert-butylcispentacin, a new cispentacin analogue) and (±)-7 (the starting racemate for 1,4-ethylene-bridged cispentacin).

Full text of DOI:10.1016/j.tetasy.2008.04.003

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 1005–1009
Vapour-assisted enzymatic hydrolysis
of b-lactams in a solvent-free system
*
}
´
Eniko Forro and Ferenc Fulop
¨ ¨
Institute of Pharmaceutical Chemistry, University of Szeged, H-6720-Szeged, Eo¨tvo¨s utca 6, Hungary
Received 29 February 2008; accepted 1 April 2008
Dedicated to Professor Laszlo Toke on the occasion of his 75th birthday
Abstract—A new, solvent-free, vapour-assisted method, developed for the synthesis of carbocyclic cis b-amino acid enantiomers through
the Candida antarctica lipase B-catalysed enantioselective (E >200) hydrolysis of b-lactams with 0.5 equiv of H2O at 70 °C, has been
demonstrated to be applicable on a preparative scale to produce ( )-2 (the starting racemate for cispentacin), ( )-3 (the starting race-
mate for 4-tert-butylcispentacin, a new cispentacin analogue) and ( )-7 (the starting racemate for 1,4-ethylene-bridged cispentacin).
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
In accordance with efforts to develop environmentally
friendly routes to enantiopure products, our present aim
is to find an economical, new b-lactam ring-opening tech-
nique for the preparation of b-amino acid enantiomers
(Scheme 1), the enzymatic reactions being performed in a
solvent-free, vapour-assisted system.
There are ever more stringent requirements for the devel-
opment of environmentally friendly, economical routes to
enantiomerically pure products. Over the past few years,
the synthesis1 of enantiopure carbocyclic b-amino acids
has received considerable attention, due to their wide-rang-
ing use in peptide,2 heterocyclic3 and combinatorial4 chem-
istry and drug research.5 For example, nitrile-hydrolysing
strains of Rhodococcus sp. have been introduced as novel
catalysts for the preparation of b-amino acid enantiomers.6
Kanerva et al. described the synthesis of several enantio-
pure carbocyclic b-amino acid derivatives, including ethyl
(1R,2S,4R)-2-amino-4-tert-butylcyclopentanecarboxylate
hydrochloride, through the lipase SP 526-catalysed enan-
tioselective N-acylation of racemic b-amino esters with
2,2,2-trifluoroethyl hexanoate. A new direct enzymatic
method that affords enantiopure b-amino acids through
the lipase-catalysed ring cleavage of carbocyclic b-lactams
has been reported,7 as has a very efficient enzymatic tech-
nique that yields enantiopure carbocyclic cis- and trans-b-
amino acids through the lipase-catalysed hydrolysis of
the corresponding b-amino esters.8 Some of the non-con-
ventional media currently used and for lipase-catalysed
reactions include organic solvents, ionic liquids and super-
critical fluids, in addition to solvent-free systems.9
2. Results and discussion
We had previously described the enzymatic resolutions of
carbocyclic b-lactams ( )-1, ( )-2 and ( )-4–( )-9
(Scheme 1) through the Lipolase (lipase B from Candida
antarctica)-catalysed ring opening of b-lactams in an or-
ganic medium (E >200).10 It was noted that the presence
of H2O at the surface of the enzyme was of key importance
in the hydrolysis of the lactam; the hydrolyses of 2, 5 and 9
in the presence of Lipolase in iPr2O, for instance, were
complete even without the addition of any H2O, since the
H2O present in the enzyme preparation was sufficient en-
ough for the b-lactam ring opening. In the light of this
important observation, we decided to perform a reaction
under solvent-free conditions and, if possible, to devise
the enantioselective ring opening of model compounds with
H2O as a nucleophile, on the principle that ‘the best solvent
is no solvent’.
*
Since the ring cleavage of the unsaturated ( )-2 in an or-
Corresponding author. Tel.: +36 62 545564; fax: +36 62 545705; e-mail:
fulop@pharm.u-szeged.hu
ganic solvent reached 50% conversion in a much shorter
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.04.003

1006
E. Forro´, F. Fu¨lo¨p / Tetrahedron: Asymmetry 19 (2008) 1005–1009
O
O
COOH
NH2
CAL-B
+
0.5 equiv. H2O
NH
NH
no solvent
( )-1-9
10-18
19-27
O
O
O
O
O
NH
( )-1
NH
NH
NH
NH
( )-5
2
( )-4
( )-
( )-3
O
O
O
O
NH
NH
NH
NH
( )-8
( )-9
6
( )-
7
( )-
Scheme 1. Enantioselective ring cleavage of b-lactams.
reaction time (5 h10a) than that for its saturated analogue
( )-1 (ꢀ10 days7), ( )-2 was chosen for preliminary
experiments. Evans et al. reported that ENZA 1 (Rhodo-
coccus equi NCIMB 40213) catalysed the hydrolysis of
( )-2 in phosphate buffer, in two steps at 20 °C, affording
the products in high enantiomeric excess (ee >96%), but
exhibited poor activity towards the saturated b-lactam
( )-1.11
the same good E and reaction rate were obtained as
when the reaction was performed in an incubator shaker
under the same conditions (Table 1, entry 3).
It should be mentioned that an attempt was made to im-
prove the enzyme:substrate mass ratio (from 4:1 to 2:1)
in the case of ( )-2; a similarly good result (E >200) was
obtained, but a longer reaction time was required (conver-
sion: 25% after 3 h).
We first performed the hydrolysis of ( )-2 in an incubator
shaker (210 rpm) with 0.5 equiv of H2O in the presence of
Lipolase at 50 °C without solvent (Table 1, entry 1). Lipo-
lase displayed activity commensurable with that observed
for the ring cleavage of ( )-2 in an organic solvent (reac-
tion in iPr2O at 60 °C: conversion 50% after 5 h).10a
Since an improvement of the enzyme:substrate mass ratio
(4:1) proved to be quite unlikely, special attention was paid
to the possibility of reusing the enzyme: the hydrolysis of
( )-2 was performed with Lipolase that had already been
used in 1, 2, 3 or 4 cycles (Table 2). The catalytic activity
of the Lipolase progressively became slightly lower,
although the enantiomeric excess of the product was appar-
ently not affected. The possibility of reusing the enzyme
therefore makes the process an economical one.
Temperature is a factor, which in certain cases affects the
enantioselectivity and the rate of enzymatic reactions. Con-
sequently, we investigated the influence of temperature on
the Lipolase-catalysed ring cleavage of ( )-2 (Table 1).
Increasing the temperature had a positive effect: the reac-
tion became faster, while the enantioselectivity remained
unchanged (Table 1, entries 2–5). Since the enzyme became
darker at 80 °C, 70 °C was chosen as the optimum temper-
ature for the preparative-scale resolution.
The hydrolyses of the other b-lactams ( )-1 and ( )-3–( )-
9 likewise exhibited excellent enantioselectivities under
these conditions (Table 3). Unexpectedly good results (E
>200) were observed for ( )-3, which contains a very lipo-
philic and bulky tert-butyl substituent at the 4-position.
The hydrolysis of ( )-2 was also performed in an ultrasonic
bath in a solvent-free system at 70 °C (Table 1, entry 4) and
The preliminary experiments clearly demonstrated that this
solvent-free method is applicable on a preparative scale for
the enantioselective ring cleavage of ( )-2, ( )-3 and ( )-7
(Scheme 2), starting racemates for cispentacin and
Table 1. Effects of temperature on the ring cleavage of ( )-2a
c
Entry Temperature Time Conversion eesb eep
E
Table 2. Conversion and enantioselectivity of the ring opening of ( )-2a
with the recycled enzyme
(°C)
(h)
(%)
(%)
(%)
1
2
3
4
5
50
60
70
70d
80
3
3
3
2.5
3
31
40
47
45
49
44
66
88
83
94
>99 >200
>99 >200
>99 >200
>99 >200
>99 >200
c
Lipolase (50 mg)
Conversion (%)
eesb (%)
eep (%)
E
Used once
44
39
35
29
78
63
53
40
>99
>99
>99
>99
>200
>200
>200
>200
Twice used
3 times used
4 times used
a 0.1 mmol substrate, Lipolase (50 mg), 0.5 equiv H2O, after 3 h.
b According to GC.10a
c According to GC after double derivatisation.10a
d Ultrasonic bath (35 kHz).
a 0.1 mmol substrate, 0.5 equiv H2O, 70 °C, after 3 h.
b According to GC.10a
c According to GC after double derivatisation.10a

E. Forro´, F. Fu¨lo¨p / Tetrahedron: Asymmetry 19 (2008) 1005–1009
Table 3. Conversion and enantioselectivity of the ring opening of ( )-1 and ( )-3-( )-8a
1007
c
Substrate
Time
Conversion (%)
eesb (%)
eep (%)
E
(
(
(
(
(
(
(
(
)-1
)-3
)-4
)-5
)-6
)-7
)-8
)-9
19 h (5 days)
19 h
19 h (5 days)
5 h
5 days
4 days
21 (50)
42
25 (50)
49
40
50
27 (98)
72
33 (98)
95
65
>99
83
>99 (>99)
>99
>99 (>99)
>99
>99
>99
>200 (>200)
>200
>200 (>200)
>200
>200
>200
5 days
4 days
46
49
>99
>99
>200
>200
94
a 0.1 mmol substrate, Lipolase (50 mg), 0.5 equiv H2O, 70 °C.
b According to GC.10
c According to GC after double derivatisation.10
O
O
COOH
CAL-B
1
2
1
5
+
0.5 equiv. H2O
NH
HN
70 ºC
NH2
no solvent
2
( )-
(1R,2S)-11
20
(1S,5R)-
O
O
COOH
NH2
CAL-B
1
2
1
3
5
+
4
0.5 equiv. H2O
70 ºC
no solvent
NH
HN
( )-3
21
(1S,3S,5R)-
(1R,2S,4R)-12
22% HCl/EtOH
22% HCl/EtOH
18% HCl,
Δ
EtOOC
Δ
HOOC
COOH
HCl·H2N
HCl·H2N
(1S,2R,4S)-
NH2·HCl
29
(1S,2R,4S)-28
(1R,2S,4R)-12·HCl
O
O
CAL-B
COOH
NH2
(1R,2R,3S,4S)-16
2
5
+
3
0.5 equiv. H2O
2
NH
HN
70 ºC
( )-7
(1R,2R,5S,6S)-25
no solvent
Scheme 2. Ring opening of b-lactams in a solvent-free system.
its 4-tert-butyl and 1,4-ethylene-bridged analogues. The
results are reported in Table 4 and in Section 4.
The transformations involving the ring opening of b-lac-
tam 21 with 18% aqueous HCl or 22% ethanolic HCl
Table 4. Lipolase-catalysed ring cleavage of ( )-2, ( )-3 and ( )-7a
Time
Conversion (%)
E
b-Lactam (20, 21 and 25)
b-Amino acid (11, 12 and 16)
25
25
Yield (%)
Isomer
eeb (%)
½aꢁD
Yield (%)
Isomer
eec (%)
½aꢁD
(
(
(
)-2
)-3
)-7
4 h
40 h
6 days
50
50
50
>200
>200
>200
47
44
44
1S,5R
1S,3S,5R
1R,2R,5S,6S
97
96
98
ꢂ33.2d
41
43
41
1R,2S
1R,2S,4R
1R,2R,3S,4S
>99
>99
>99
+99.6e,f
ꢂ6h
+54g
+122.1d
ꢂ12.3e,i
a Enzyme:substrate mass ratio 4:1, 0.5 equiv H2O, 70 °C.
b According to GC.
c According to GC after double derivatisation.
d c 0.35, CHCl3.
e c 0.3, H2O.
25
½aꢁD ¼ þ96:7 (c 0.3, H2O).10a
f
g c 0.25, EtOH.
h c 0.2, H2O.
25
½aꢁD ¼ ꢂ12:2 (c 0.4, H2O).10b
i

1008
E. Forro´, F. Fu¨lo¨p / Tetrahedron: Asymmetry 19 (2008) 1005–1009
resulted in the corresponding enantiomer of the b-amino
acid hydrochloride 29 (ee = 96%) or b-amino ester hydro-
chloride 28 (ee = 95%), respectively. Treatment of amino
acid 12 with 22% HCl/EtOH resulted in enantiopure
12ꢃHCl (ee >99%) (Scheme 2).
ester 27 was determined by using the same chiral column
after derivatisation with acetic anhydride in the presence
of 4-dimethylaminopyridine and pyridine (190 °C isother-
mal; 100 kPa; retention times (min): 27: 9.82, antipode:
9.62). Enantioselectivity (E) was calculated using the equa-
tion E = {ln[(1 ꢂ ees)/(1 + ees/eep)]}/{ln[(1 + ees)/(1 + ees/
eep)]}.14 Optical rotations were measured with a Perkin–
Elmer 341 polarimeter. H NMR spectra were recorded
on a Bruker Avance DRX 400 spectrometer. Melting
points were determined on a Kofler apparatus.
The chromatograms analysed indicated that CAL-B dis-
1
plays the same enantiopreference for all these b-lactams
in the solvent-free system and in iPr2O.7,8,10 The value of
25
½aꢁD ¼ þ4 (c 0.14, EtOH) for 28 and the literature value12
for ethyl (1R,2S,4R)-2-amino-4-tert-butylcyclopentane-
20
carboxylate hydrochloride, ½aꢁD ¼ ꢂ2:4 (c 1, EtOH), are
4.2. Preparative-scale resolution of 6-azabicyclo[3.2.0]hept-
3-en-7-one, ( )-2
in accordance with this.
Crystalline racemic 1 (500 mg, 4.58 mmol) was mixed well
with Lipolase (2 g), after which water (41 lL, 2.29 mmol)
was added, and the mixture was shaken in an incubator
shaker at 70 °C for 4 h. First the unreacted b-lactam was
washed off the surface of the enzyme with EtOAc
(3 ꢄ 15 mL), and this was followed by the washing off of
3. Conclusions
An economical, facile and solvent-free enzymatic method
has been developed for the preparation of enantiopure car-
bocyclic b-amino acids. The method is equally applicable
for the enantioselective ring opening of mono- and bicyclic
saturated and unsaturated, and tricyclic b-lactams, with
0.5 equiv of H2O as the only reagent. Excellent enantio-
selectivities (E >200) were observed for the ring cleavage
of ( )-1–( )-9 at 70 °C, even with Lipolase that had
already been used four times. The hydrolysis of ( )-3
resulted in (1R,2S,4R)-b-amino acid (a new cispentacin
analogue; ee >99%) and (1S,3S,5R)-b-lactam (ee = 96%).
The products can be easily separated.
b-amino acid with distilled water (3 ꢄ 15 mL): (1S,5R)-20
25
{235 mg, 47%; ½aꢁD ¼ ꢂ33:2 (c 0.35, CHCl3); mp 74–
75 °C, ee = 97%} and (1R,2S)-11 {237 mg, 41%;
25
½aꢁD ¼ þ99:6 (c 0.3, H2O); mp >240 °C; ee >99%}. The
1H NMR data on the products were identical with those
given in the literature.10a
4.3. Small-scale resolution of (1S*,3S*,5R*)-3-tert-butyl-6-
azabicyclo[3.2.0]heptan-7-one, ( )-3
Following the procedure described above, the reaction of
4. Experimental
racemic 3 (100 mg, 0.59 mmol) and H2O (6 lL, 0.33 mmol)
in the presence of Lipolase (400 mg) at 70 °C afforded
25
4.1. Materials and methods
(1S,3S,5R)-21 {44 mg, 44%; ½aꢁD ¼ þ54 (c 0.25, EtOH);
mp 136–138 °C; ee = 96%} and (1R,2S,4R)-12 {47 mg,
25
Lipolase (lipase B from C. antarctica), produced by sub-
merged fermentation of a genetically modified Aspergillus
oryzae microorganism and adsorbed on a macroporous
resin, was purchased from Sigma–Aldrich. The carbocyclic
b-lactams were prepared according to the literature.7,10,13
43%; ½aꢁD ¼ ꢂ6 (c 0.2, H2O); mp 220–222 °C; ee >99%}
in 40 h. When (1R,2S,4R)-12 (20 mg) was treated with
22% HCl/EtOH (3 mL), (1R,2S,4R)-12 HCl [21 mg, 78%;
25
½aꢁD ¼ ꢂ5 (c 0.15, H2O); mp 226–229 °C, ee >99%] was
formed. When (1S,3S,5R)-21 (20 mg) was refluxed in 18%
HCl or 22% HCl/EtOH (5 mL) for 3 h, white crystals of
25
In a typical small-scale experiment, a racemic b-lactam
(0.1 mmol) and Lipolase (25 or 50 mg of a new charge,
or material that had already been used in 1, 2, 3 or 4 cycles)
were mixed well, and H2O (0.5 equiv) was then added. The
mixture was shaken at 50 °C, 60 °C, 70 °C or 80 °C. The
progress of the reaction was followed by taking samples
from the reaction mixture at intervals and analysing them
by gas chromatography. The ee values for the unreacted
b-lactam and the b-amino acid enantiomers produced were
determined by gas chromatography on Chromopak Chiral-
sil-Dex CB or Chirasil-L-Val columns, as described ear-
lier.8,10 The ee value for the new enantiomeric lactam 21
was determined on a Chromopak Chiralsil-Dex CB column
(190 °C isothermal; 100 kPa; retention times (min): 21:
5.91, antipode: 5.63), while the ee value for amino acid
12 produced was determined by using the same chiral col-
umn after double derivatisation with (i) diazomethane; (ii)
acetic anhydride in the presence of 4-dimethylaminopyr-
idine and pyridine (120 °C for 10 min ? 180 °C (rate of
temperature rise 10 °C/min; 100 kPa); retention times
(min): 12: 21.26, antipode: 21.12). The ee value for amino
(1S,2R, 4S)-29 [20 mg, 67%; ½aꢁD ¼ þ5 (c 0.25, H2O); mp
225–227 °C; ee = 96%] or (1S,2R,4S)-28 [19 mg, 63%;
½aꢁD ¼ þ4 (c 0.14, EtOH); ee = 95%], were obtained.
1H NMR (400 MHz, D2O) d (ppm) for 12: 0.78 (9H, s,
3 ꢄ CH3) 1.75–2.05 (5H, m, 2 ꢄ CH2 and CHC(CH3)3)
2.77–2.82 (1H, m, H-1) 3.62–3.68 (1H, m, H-2). Anal.
Calcd for C10H19NO2: C, 64.83; H, 10.34; N, 7.56. Found:
C, 64.99; H, 10.30; N, 7.56.
25
1H NMR (400 MHz, D2O) d (ppm) for 12ꢃHCl and for 29:
the data for the two compounds were identical: 0.91 (9H, s,
3 ꢄ CH3) 1.32–1.35 (3H, t, J = 7.1, CH2CH3) 1.85–2.15
(5H, m, 2 ꢄ CH2 and CHC(CH3)3) 3.22–3.28 (1H, m,
H-1) 3.90–3.95 (1H, m, H-2) 4.28 (2H, m, CH2CH3). Anal.
Calcd for C10H19NO2ꢃHCl: C, 54.17; H, 9.09; N, 6.32.
Found: C, 54.04; H, 9.00; N, 6.41.
1H NMR (400 MHz, CDCl3) d (ppm) for 21: 0.91 (9H, s,
3 ꢄ CH3), 1.28–1.34 and 2.00–2.09 (4H, m, 2 ꢄ CH2),
1.80–1.85 (1H, dd, J = 13.4, 5.6, CHC(CH3)3), 3.53–3.56

E. Forro´, F. Fu¨lo¨p / Tetrahedron: Asymmetry 19 (2008) 1005–1009
1009
(d) Liljeblad, A.; Kanerva, L. T. Tetrahedron 2006, 62, 5831;
(1H, m, H-1), 4.06–4.08 (1H, m, H-2), 5.54 (1H, br s, NH).
Anal. Calcd for C10H17NO: C, 71.81; H, 10.25; N, 8.37.
Found: C, 71.71; H, 10.18; N, 8.32.
´
(e) Forro, E.; Fulo¨p, F. Mini Rev. Org. Chem. 2004, 1, 931.
¨
2. (a) Price, J. L.; Horne, W. S.; Gellman, S. H. J. Am. Chem.
´
Soc. 2007, 129, 6376; (b) Martinek, T. A.; Mandity, I. M.;
´
´
´
Fulo¨p, L.; Toth, G. K.; Vass, E.; Hollosi, M.; Forro, E.;
¨
¨
1H NMR (400 MHz, D2O) d (ppm) for 28: 0.91 (9H, s,
3 ꢄ CH3) 1.33 (3H, t, J = 7.1 Hz, CH2CH3) 1.94–2.26
(5H, m, 2 ꢄ CH2 and CHC(CH3)3) 3.22–3.28 (1H, m,
H-1) 3.90–3.95 (1H, m, H-2) 4.24–4.31 (2H, m, CH2CH3).
Anal. Calcd for C12H23NO2ꢃHCl: C, 57.70; H, 9.68; N,
5.61. Found: C, 57.60; H, 9.64; N, 5.56.
Fulo¨p, F. J. Am. Chem. Soc. 2006, 128, 13539.
3. (a) Carter, P. H. U.S. Patent 2005,277,666; Chem. Abstr.
´
2005, 144, 51452; (b) Gyonfalvi, S.; Szakonyi, Z.; Fulo¨p, F.
Tetrahedron: Asymmetry 2003, 14, 3965; (c) Kapferer, P.;
Vasella, A. Helv. Chim. Acta 2004, 87, 2764.
¨
´
4. (a) Kanizsai, I.; Gyonfalvi, S.; Szakonyi, Z.; Sillanpa¨a¨, R.;
´
Fulo¨p, F. Green Chem. 2007, 9, 357; (b) Kiss, L.; Forro, E.;
¨
Sillanpa¨a¨, R.; Fulo¨p, F. J. Org. Chem. 2007, 72, 8786.
¨
4.4. Preparative-scale resolution of exo-3-azatricyclo-
[4.2.1.0[2.5]]non-7-en-4-one, ( )-7
5. (a) Enantioselective Synthesis of b-Amino Acids; Juaristi, E.,
Soloshonok, V. A., Eds.; Wiley-Interscience: New York,
2005; (b) Mowery, B. P.; Lee, S. E.; Kissounko, D. A.;
Epand, R. F.; Epand, R. M.; Weisblum, B.; Stahl, S. S.;
Gellman, S. H. J. Am. Chem. Soc. 2007, 129, 15474; (c)
Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron:
Asymmetry 2005, 16, 2833.
Following the procedure described above, the reaction of
racemic 7 (500 mg, 3.7 mmol) and H2O (34 lL, 1.88 mmol)
in the presence of Lipolase (2 g) at 70 °C afforded
25
(1R,2R,5S,6S)-25 {220 mg, 44%; ½aꢁD ¼+122.1 (c 0.35,
CHCl3); mp 90–93 °C; ee = 98%} and (1R,2R,3S,4S)-14
´
6. Winkler, M.; Martinkova, L.; Knall, A. C.; Krahulec, S.;
25
{232 mg, 41%; ½aꢁD ¼ ꢂ12:3 (c 0.3, H2O); mp >260 °C; ee
Klempier, N. Tetrahedron 2005, 61, 4249.
>99%} in 6 days. The 1H NMR data on the products were
identical with those given in the literature.10b
´
7. Forro, E.; Fulo¨p, F. Org. Lett. 2003, 5, 1273.
¨
´
8. Forro, E.; Fulo¨p, F. Chem. Eur. J. 2007, 22, 6397.
¨
9. (a) Sheldon, R. A. Green Chem. 2007, 9, 357; (b) Foresti, M.
´
I.; Pedernera, M.; Bucala, V.; Ferreira, M. L. Enzyme
Microb. Technol. 2007, 41, 62.
Acknowledgements
´
10. (a) Forro, E.; Fulo¨p, F. Tetrahedron: Asymmetry 2004, 15,
¨
´
2875; (b) Forro, E.; Fulo¨p, F. Tetrahedron: Asymmetry 2004,
¨
The authors acknowledge the receipt of OTKA grants K
71938 and T 049407 and a Bolyai Fellowship for EF.
´
15, 573; (c) Forro, E.; Fulo¨p, F. Chem. Eur. J. 2006, 12, 2587.
11. Evans, C.; McCague, R.; Roberts, S. M.; Sutherland, A. G.;
¨
Wisdom, R. J. Chem. Soc., Perkin Trans. 1 1991, 2276.
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