Chemoenzymatic preparation of fluorine-substituted β-lactam enantiomers exploiting Burkholderia cepacia lipase

Article abstract of DOI:10.1016/j.tetasy.2007.10.003

Both enantiomers of fluorinated and non-fluorinated 4-phenyl-2-azetidinones are prepared in high enantiopurities (ee 99%) by a chemoenzymatic method, using a double resolution technique to N-hydroxymethylated β-lactams in the presence of Burkholderia cepa

Full text of DOI:10.1016/j.tetasy.2007.10.003

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2468–2472
Chemoenzymatic preparation of fluorine-substituted b-lactam
enantiomers exploiting Burkholderia cepacia lipase
Xiang-Guo Li and Liisa T. Kanerva*
Department of Pharmacology, Drug Development and Therapeutics/Laboratory of Synthetic Drug Chemistry and Department of Chemistry,
University of Turku, Lemminkaisenkatu 5C, FIN-20520 Turku, Finland
Received 31 August 2007; accepted 2 October 2007
Abstract—Both enantiomers of fluorinated and non-fluorinated 4-phenyl-2-azetidinones are prepared in high enantiopurities (ee 99%) by
a chemoenzymatic method, using a double resolution technique to N-hydroxymethylated b-lactams in the presence of Burkholderia cepacia
lipase as the source of enantiopurity. N-Deprotections yield the b-lactam enantiomers from the corresponding hydroxymethylated
counterparts using KMnO4 in a mixture of acetone and water.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
the hydrogen atoms with isosteric fluorine in the b-lactam
skeleton can further enhance their importance for medici-
nal chemistry, often leading to derivatives with desirable
effects on physiological activity and metabolism. The
(S)-enantiomer of 3,3-difluoro-4-phenyl-2-azetidinone
(S)-1a (Scheme 1) is a good example of an activated acyl
b-Lactams (2-azetidinones) are important chiral intermedi-
ates and building blocks for various types of pharmaceuti-
cals, the preparation of which are thoroughly described in a
number of reviews.1–7 The substitution of one or more of
R
Step 2.
PS-D
O
R
Step 1.
(CHO)n
O
R
R
O
O
R1
R1
R1
R1
3
4
2
N
+
NH
N
N
ultrasound
OH
Vinyl butanoate
Toluene
OH
O
Pr
O
(S)-3a, ee 89 %
rac-2a
(R)-2a, ee 99 %
rac-1a
(3S,4S)-3b, ee 70 %
(R)-3c, ee 94 %
rac-2b (trans)
rac-2c
(3R,4R)-2b, ee 99 %
(S)-2c, ee 99 %
rac-1b (trans)
rac-1c
PS-D
BuOH
Step 4.
Step 3.
KMnO4
DIPE
R
O
R
O
R
O
R1
R1
R1
Step 3.
KMnO4
HN
NH
N
HO
(S)-2a, ee 99 %
(S)-1a, ee 99 %
(R)-1a, ee 99 %
(3S,4S)-2b, ee 99 %
(R)-2c, ee 99 %
(3S,4S)-1b, ee 99 %
(R)-1c, ee 99 %
(3R,4R)-1b, ee 99 %
(S)-1c, ee 99 %
Scheme 1. Chemoenzymatic preparation of enantiopure lactams: (a) R = R1 = F, (b) R = F, R1 = H and (c) R = R1 = H.
*
Corresponding author. Tel.: +358 2 333 6773; fax: +358 2 333 7955; e-mail: lkanerva@utu.fi
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.10.003

X.-G. Li, L. T. Kanerva / Tetrahedron: Asymmetry 18 (2007) 2468–2472
2469
donor which, as was shown previously for the reaction of
N-Boc activated b-lactams with alcohols,5,6,8 likely gives
fluorotaxol analogues when coupled with the free alcohol
group of the taxane ring.
tion of the b-lactam structure.12 Non-fluorinated rac-1c
was prepared as reported using the 1,2-dipolar cyclo-
addition of chlorosulfonyl isocyanate (CSI) to styrene.14
N-Hydroxymethylation of the b-lactams with paraform-
aldehyde under ultrasound easily afforded racemic 2a–c as
substrates for lipase-catalyzed O-acylation (Scheme 1).14,15
Lipases are very versatile biocatalysts for the production of
enantiopure compounds, which in the best cases can afford
both enantiomers at the same time through kinetic resolu-
tion. Enantioselective hydrolysis and alcoholysis of the
b-lactam ring with lipase catalysis has proven to be an
applicable kinetic resolution method, producing the less
reactive enantiomer as a b-lactam.9–12 We had previously
shown that the kinetic resolution of fluorine-activated
b-lactams (4-phenyl-2-azetidinones rac-1a and rac-1b,
Scheme 1) as acyl donors with alcohols and Burkholderia
cepacia lipase (commercial lipase PS-D or lipase PS as
adsorbed on Celite in the presence of sucrose13) affords
the corresponding enantiopure (S)-b-amino esters, leaving
the (R)-b-lactams (R)-1a and (3R,4R)-1b unreacted.12
Another widely used lipase-catalyzed kinetic resolution
method exploits N-hydroxymethylated b-lactams as race-
mic alcohols for O-acylation, including the preparation of
the enantiomers of rac-1c.9,10,14,15 The benefit of the latter
method is that the kinetic resolution leaves the b-lactam
ring of both enantiomers untouched.
There are two key steps in the chemoenzymatic synthesis of
the b-lactam enantiomers 1a–c: lipase-catalyzed kinetic re-
solution of rac-2a–c through step 2 and N-deprotection of
enantiomers 2a–c through step 3 (Scheme 1). When enzy-
matic enantioselectivity does not provide excellent results,
a double resolution technique with the minimal number
of reaction steps proved to be the best choice for the
preparation of both enantiomers of a racemic alcohol. This
can be conveniently carried out by performing the first enzy-
matic acylation followed by enzymatic alcoholysis of the
ester produced.15 The acylation conditions were previously
optimized for the kinetic resolution of rac-2c, except that
our catalyst now is commercial lipase PS-D. Accordingly,
rac-2a–c was subjected to acylation with vinyl butanoate
and lipase PS-D in dry toluene at room temperature. Vinyl
butanoate was used in 4 equiv rather than in more usual
2 equiv excess in order to minimize the risk of the enzy-
matic hydrolysis of the formed 3a–c back to the corre-
sponding 2a–c by the water in the seemingly dry enzyme
preparation and to obtain the unreacted substrate
smoothly in an enantiopure form.15 Two enzyme contents
(15 and 20 mg mLꢀ1) were tested. Although the enzyme
contents had an effect on the reactivity, they both conve-
niently gave enantioselective reactions, leading to unre-
acted enantiomers in enantiopure forms at reasonable
times (Table 1). The same high enantioselectivity (enantio-
meric ratio, E > 200) is clear for the acylation of rac-2c
with lipase PS-D (rows 4 and 5) and with the lipase PS
preparation (row 6). The presence of fluorine in rac-2a
and rac-2b lowers the enantioselectivity for the acylation.
For effective sequential gram-scale resolution, the acyla-
tions with 15 mg mLꢀ1 for rac-2b and rac-2c and
20 mg mLꢀ1 for rac-2a were stopped when the unreacted
enantiomers were enantiopure at 58% and 51% and 53%
conversions (rows 1, 2 and 4), respectively. Separation of
the resolution products on a silica gel column yielded the
unreacted (R)-2a, (3R,4R)-2b and (S)-2c with the desired
ee = 99%.
Herein we report the chemoenzymatic preparation of both
enantiomers of b-lactams 1a and 1b (Scheme 1). The key
racemates for kinetic resolution are N-hydroxymethylated
b-lactams, rac-2a and rac-2b. Special emphasis is needed
for the chemical N-deprotection of the prepared 2a and
2b enantiomers through step 3 in such a way that the ring
opening of the fluorine activated rings can be prevented.
The non-fluorinated 1c is included in the present work in
order to obtain comparable data based on the use of lipase
PS-D catalysis. In addition, the double kinetic resolution
technique now exploited has not been used before for the
preparation of (R)- and (S)-2c. The asymmetric acylation
of rac-2c, which gives the unreacted (S)-2c, and the asym-
metric alcoholysis of the corresponding racemic ester which
gives the produced (R)-2c, have earlier produced the
enantiomers.14
2. Results and discussion
A simple chemoenzymatic protocol to provide the enantio-
mers of rac-1a–c in enantiopure forms (ee 99%) is shown in
Scheme 1. Fluorine-substituted rac-1a and -1b used as
starting materials were available from our previous work
whereby a Reformatsky type reaction allowed the forma-
In addition to enantiopure 2a–c, enantiomerically enriched
esters 3a–c were produced by lipase PS-D-catalyzed acyla-
tion (Table 1). In the next step, the isolated 3a–c were
transformed into the corresponding enantiopure alcohols
under mild and enantiomeric excess increasing conditions,
Table 1. Kinetic resolution of rac-2a–c with vinyl butanoate (4 equiv) in toluene at room temperature
Row
Substrate
Lipase (mg mLꢀ1
)
Time (h)
Conversion (%)
ee2 (%) (abs. config.)
ee3 (%) (abs. config.)
E
1
2
3
4
5
6
2a
2b
2b
2c
20
15
20
15
20
30
1
53
99 (R)
89/(S)
90
19
18
>200
>200
>200
1/2.3
1/1.5
1/1.5
1/1.5
1.5
30/58
41/50
49/51
50/51
49
37/99 (3R,4R)
56/76 (3R,4R)
95/99 (S)
97/99 (S)
94/(S)
86/70 (3S,4S)
82/76 (3S,4S)
99/94 (R)
98/95 (R)
97/(R)
2c
2ca
a Vinyl butanoate (2 equiv), lipase PS on Celite in the presence of sucrose;13 see Ref. 14.

2470
X.-G. Li, L. T. Kanerva / Tetrahedron: Asymmetry 18 (2007) 2468–2472
Table 2. Alcoholysis of enantiomerically enriched 3a–c with butanol (2 equiv) in DIPE in the presence of lipase PS-D (30 mg mLꢀ1) at room temperature
Row
Substrate [ee (%)]
Time (h)
Conversion (%)
ee2 (%) (abs. config.)
1
2
3
(S)-3a [89]
(3S,4S)-3b [70]
(R)-3c [94]
1.7
4.2
1.0
92
83
94
99 (S)
99 (3S,4S)
99 (R)
by subjecting the esters to alcoholysis with 1-butanol in
diisopropyl ether (DIPE) in the presence of lipase PS-D
(Scheme 1, step 4; Table 2). The reaction conditions corre-
sponded to those previously used when the enantiomeri-
cally enriched 4-benzyl-substituted analogue of 3c was
transformed into the corresponding enantiopure alcohol
by lipase PS catalysis.15 A low butanol concentration
(2 equiv) allowed high reactivity. The reactions were car-
ried out to the stage (82–94% conversion depending on
the initial ee of the ester) where the 2 produced was still
enantiopure. As a total outcome of the double resolution,
45% of rac-2a was transformed into (R)-2a and 42% into
(S)-2a; 41% of rac-2b was transformed into both (3R,4R)-
2b and (3S,4S)-2b; and finally, 49% of rac-2c was trans-
formed into (R)-2c and 47% into (S)-2c. These values
closely correspond to the theoretical 50% proportions of
the enantiomers in the racemates.
3. Conclusion
In conclusion, the chemoenzymatic route shown in Scheme
1 describes a highly effective method to prepare both enan-
tiomers of the b-lactams 1a–c. Although the enantioselec-
tivities in the case of kinetic resolution through acylation
only range from moderate to good, a double resolution
technique allows the transformation of racemates to enan-
tiopure (ee 99%) counterparts with close to theoretical
yields.
4. Experimental
4.1. Materials and methods
All solvents were of the highest analytical grade and were
dried by standard methods. Compounds rac-1a and rac-
1b (with the trans-configuration) were available from our
previous work.12 Compound rac-1c and rac-2c were pre-
pared as previously reported with identical spectroscopic
properties to those in the literature.14 Lipase PS-D (immo-
bilized on Celite) from B. cepacia (previously lipase PS
from Pseudomonas cepacia) was purchased from Amano
Europe, England. Preparative chromatographic separa-
tions were performed by column chromatography on
Merck Kieselgel 60 (0.063–0.200 lm). TLC was carried
out with Merck Kieselgel 60F254 sheets. All enzymatic reac-
tions were performed at room temperature (23 ꢁC). Melting
points were measured on a Sanyo instrument.
The transformation of N-hydroxymethylated b-lactams 2
into the corresponding b-lactams 1 is another key step of
the present work. This is usually carried out using
NH4OH/MeOH treatment.10,14,15 When the transforma-
tion of the fluorine activated 2a with NH4OH/MeOH did
not give product 1a, it was clear that another method
had to be found. Oxidative cleavage with KMnO4 was pre-
viously reported to lead to the formation of free b-lactams
from the N-formyl protected compounds.16 On the other
hand, oxidation of primary alcohols with KMnO4 is
known to give aldehydes.17 Inspired by these two prece-
dents, we expected that oxidative N-deprotection with
KMnO4 would be a suitable procedure in the present work
as shown in Scheme 2. In practice, enantiomers 2a–c were
successfully transformed into the corresponding 1a–c
using KMnO4 (2 equiv) as an oxidant in the mixture of ace-
tone and water without a sign of racemization. However,
the transformation became progressively slower when
decreasing the number of fluorines in the ring. Thus, the
formation of (R)- and (S)-1c was only about 20% in
seven days, although for the last two days, the reaction
proceeded at room temperature rather than at normal
2 ꢁC. On the other hand, (R)- and (S)-1c were obtained
at 86–89% isolated yield in 20 h under the NH4OH/MeOH
treatment.
The progress of the reactions (4-fluorophenyl acetonitrile
as an internal standard) was followed by taking samples
from the reaction mixture. Theoretical yields for each of
the resolution products are based on the conversion where
the reaction was stopped. The products were analyzed in
the case of 1a, 1b, 2a, 2b and 3a by HPLC on a CHIRA-
CEL-OD column (0.46 · 25 cm) and in the case of 1c, 2c,
3b and 3c by GC on a Chrompack CP-Chirasil-DEX CB
column. The H and 13C NMR spectra were recorded on
1
a Bruker 500 spectrometer with tetramethylsilane (TMS)
as an internal standard. 1H–1H COSY, 1H–13C HQSC
and H–13C HMBC spectra were used for the assignment
1
R
R
R
O
O
O
R1
R1
R1
KMnO4
KMnO4
N
N
NH
OH
CHO
2a, R=R1=F
1a, R=R1=F
2b, R=F, R1=H
2c, R=R1=H
1b, R=F, R1=H
1c, R=R1=H
Scheme 2. N-Deprotection of 2 with KMnO4.

X.-G. Li, L. T. Kanerva / Tetrahedron: Asymmetry 18 (2007) 2468–2472
2471
of the chemical shifts when necessary. Mass spectra were
taken on a VG 7070E mass spectrometer. Optical rotations
were determined with a Perkin–Elmer polarimeter, and [a]D
obtained by changing the eluent to petroleum ether/ethyl
acetate (4:1).
values are given in units of 10ꢀ1 deg cm2 gꢀ1
.
Compound (S)-3a (676 mg, 2.39 mmol, ee = 89%) was dis-
solved in DIPE (48 mL), and BuOH (356 mg, 4.80 mmol)
and PS-D (30 mg mLꢀ1) were added. The reaction was
stopped after 1.7 h by filtering off the enzyme at 92% con-
version. The solvent was evaporated off and the residue
separated on a silica gel column as above to afford (S)-2a
(421 mg, 1.98 mmol, isolated yield 90%, ee(S)-2a = 99%)
and (R)-3a (50 mg, 0.18 mmol, ee(R)-3a = 80%).
4.2. Preparation of racemic rac-2a and rac-2b
Compound rac-1a (240 mg, 1.31 mmol) was dissolved in
tetrahydrofuran (3 mL) and paraformaldehyde (44 mg,
1.48 mmol), K2CO3 (18 mg, 0.13 mmol) and H2O
(124 mg, 6.89 mmol) were added. The suspension was
sonicated for 2 h. The solvent was evaporated off and the
residue dissolved in diethyl ether (6 mL), dried over
anhydrous Na2SO4 and filtered. After evaporation, the res-
idue was purified on a silica gel column eluting with ethyl
acetate/petroleum ether (4:1, v/v) to afford rac-2a as a solid
4.4. Preparation of (3R,4R)- and (3S,4S)-2b by
lipase-catalyzed acylation/deacylation
1
(258 mg, 1.21 mmol, yield 92%, mp 72–73 ꢁC). H NMR
Compound rac-2b (490 mg, 2.51 mmol) was dissolved in
toluene (50 mL), and lipase PS-D (15 mg mLꢀ1) and vinyl
butanoate (1.1 g, 10.00 mmol) were added. The reaction
was stopped after 2.3 h by filtering off the enzyme at 58%
conversion. The solvent was evaporated off and the residue
purified on a silica gel column with petroleum ether/ethyl
(500 MHz, CDCl3) d 3.58 (br s, 1H, OH), 4.43–4.45 (d,
J = 11.5 Hz, 1H), 5.18–5.21 (m, 2H), 7.32–7.48 (m, 5H,
arom.); 13C NMR (126 MHz, CDCl3) d 63.60, 67.48–
67.89 (t, J = 25.2 Hz), 118.19–122.83 (t, J = 293.0 Hz),
127.13, 127.99, 129.11, 129.96, 161.24–161.73 (t,
J = 31.4 Hz). HRMS: M+ found (M+ calcd for
C10H9F2NO2) 213.060200 (213.060135); MS: m/z (relative
intensity) 213 (0.15), 183 (2), 140 (100), 104 (6).
acetate (8:1) to afford (3S,4S)-3b (373 mg, 1.41 mmol,
22
isolated yield 96%, ee(3S,4S)-3b = 70%, ½aꢁD ¼ ꢀ6:0 (c 0.80,
1
CHCl3)) as an oily product. H NMR (500 MHz, CDCl3)
d 0.90–0.93 (t, J = 7.5 Hz, 3H), 1.56–1.62 (m, 2H), 2.22–
2.30 (m, 2H), 4.79–4.81 (dd, J = 11.5 Hz, 2.0 Hz, 1H),
4.87–4.89 (d, J = 11.0 Hz, 1H), 5.22–5.33 (dd,
J = 54.0 Hz, 2.0 Hz, 1H), 5.35–5.37 (d, J = 11.0 Hz, 1H),
7.28–7.33 (m, 2H), 7.39–7.46 (m, 3H). HRMS: M+ found
(M+ calcd for C14H16FNO3) 265.113700 (265.111422);
MS: m/z (relative intensity) 265 (0.05), 178 (6), 135 (23),
122 (100), 91 (10), 77 (3). (3R,4R)-2b (202 mg, 1.03 mmol,
isolated yield 98%, ee(3R,4R)-2b = 99%) was obtained by
changing the eluent to petroleum ether/ethyl acetate (1:1).
Using the above procedure, rac-2b was obtained as a semi-
solid product in 90% isolated yield. H NMR (500 MHz,
1
CDCl3) d 4.12 (br s, 1H, OH), 4.23–4.25 (d, J = 11.5 Hz,
1H), 4.91–4.94 (dd, J = 11.0 Hz, 1.0 Hz, 1H), 5.12–5.14
(d, J = 11.5 Hz, 1H), 5.17–5.29 (dd, J = 54.0 Hz, 1.5 Hz,
1H), 7.30–7.48 (m, 5H, arom.); 13C NMR (126 MHz,
CDCl3) d 61.75–61.94 (d, J = 23.9 Hz), 63.71–63.73 (d,
J = 2.5 Hz), 96.73–98.53 (d, J = 226.4 Hz), 126.76,
129.27, 129.35, 134.31, 164.44, 164.62 (d, J = 22.6 Hz).
HRMS: M+ found (M+ calcd for C10H10FNO2)
195.069700 (195.069557); MS: m/z (relative intensity) 195
(0.03), 178 (3), 135 (3), 122 (100), 91 (4), 77 (5).
Compound (3S,4S)-3b (360 mg, 1.36 mmol, ee = 70%) was
dissolved in DIPE (27 mL), and BuOH (200 mg,
2.70 mmol) and PS-D (30 mg mLꢀ1) were added. The reac-
tion was stopped after 4.2 h by filtering off the enzyme at
83% conversion. The solvent was evaporated off and the
residue was separated on a silica gel column as above to
afford (3S,4S)-2b (199 mg, 1.02 mmol, isolated yield 90%,
ee(3S,4S)-2b = 99%) and unreacted (3R,4R)-3b (60 mg,
0.23 mmol, ee(3R,4R)-3b = 71%).
4.3. Preparation of (R)- and (S)-2a by lipase-catalyzed
acylation/deacylation
Compound rac-2a (1.0 g, 4.70 mmol) was dissolved in tol-
uene (94 mL), and lipase PS-D (20 mg mLꢀ1) and vinyl
butanoate (2.1 g, 18.80 mmol) were added. The reaction
was stopped after 1 h by filtering off the enzyme at 53%
of the conversion. The solvent was evaporated off and
the residue purified on a silica gel column with petroleum
ether/ethyl acetate (12:1) to afford (S)-3a {676 mg,
4.5. Preparation of (R)- and (S)-2c by lipase-catalyzed
acylation/deacylation
2.39 mmol, isolated yield, 96%, mp 54–55 ꢁC, ee(S)-3a
=
22
89%, ½aꢁD ¼ þ49:1 (c 0.65, CHCl3)}. 1H NMR
(500 MHz, CDCl3) d 0.90–0.93 (t, J = 7.5 Hz, 3H), 1.56–
1.63 (m, 2H), 2.20–2.31 (m, 2H), 5.00–5.02 (d,
J = 11.5 Hz, 1H), 5.05–5.07 (dd, J = 8.0, 2.5 Hz, 1H),
5.43–5.46 (d, J = 11.5 Hz, 1H), 7.31–7.33 (m, 2H), 7.44–
7.46 (m, 3H). 13C NMR (126 MHz, CDCl3) d 13.53,
18.06, 35.53, 62.44 (t, J = 2.5 Hz), 69.74 (t, J = 23.9 Hz),
121.04, 128.09, 129.08, 130.02, 130.11, 161.08, 173.05.
HRMS: M+ found (M+ calcd for C14H15F2NO3)
283.102700 (283.102000); MS: m/z (relative intensity) 283
(0.01), 206 (0.05), 153 (5), 140 (100), 91 (4). (R)-2a
(447 mg, 2.10 mmol, isolated yield 95%, ee = 99%) was
Compound rac-2c (1.2 g, 6.72 mmol) was dissolved in tolu-
ene (134 mL), and lipase PS-D (15 mg mLꢀ1) and vinyl
butanoate (3.1 g, 26.89 mmol) were added. The reaction
was stopped after 1.5 h by filtering off the enzyme at 51%
of the conversion. The solvent was evaporated off and
the residue purified on a silica gel column with petroleum
ether/ethyl acetate (6:1) to afford an oily product (R)-3c
{820 mg, 3.32 mmol, isolated yield 97%, ee(R)-3c = 94%,
22
½aꢁD ¼ þ61:3 (c 1.00, EtOH)}. (S)-2c (554 mg, 3.13 mmol,
isolated yield 95%, ee(S)-2c = 99%, mp 85–87 ꢁC) was ob-
tained by changing the eluent to petroleum ether/ethyl ace-
tate (1:3). The spectroscopic data are as reported.14

2472
X.-G. Li, L. T. Kanerva / Tetrahedron: Asymmetry 18 (2007) 2468–2472
Compound (R)-3c (789 mg, 3.19 mmol, ee = 94%) was dis-
solved in DIPE (64 mL), and BuOH (474 mg, 6.40 mmol)
and PS-D (30 mg mLꢀ1) were added. The reaction was
stopped after 1 h by filtering off the enzyme at 94% conver-
sion. The solvent was evaporated off and the residue was
separated on a silica gel column as above to afford (R)-2c
(509 mg, 2.88 mmol, isolated yield 96%, ee(R)-2c = 99%)
and rac-3c (33 mg, 0.13 mmol).
(S)-1c (isolated yield 23%, mp 108–109 ꢁC, ee(S)-1c = 99%)
with the specific rotations shown in Table 3.
Compounds (R)- and (S)-1c were also prepared by adding
NH4OH (1 mL, 25% in water) to a solution of the corre-
sponding 2c enantiomer (100 mg, 0.56 mmol, ee = 99%)
in methanol (10 mL). The reaction proceeded for 20 h at
room temperature before the solvents were evaporated.
The residue was purified on silica gel column using ethyl
acetate in petroleum ether [33% (v/v)], affording (R)-1c
(71 mg, 0.48 mmol, isolated yield 86%, ee(R)-1c = 99%)
and (S)-1c (89% isolated yield, ee(S)-1c = 99%), respectively.
4.6. Preparation of (R)- and (S)-1a, (3R,4R)- and (3S,4S)-1b
and (R)-1c and (S)-1c
Compound (S)-2a (85 mg, 0.40 mmol, ee = 99%) was
added to a solution of KMnO4 in acetone (32 mL) and
H2O (32 mL) at room temperature. Immediately after the
addition, the reaction mixture was put into a fridge at
2 ꢁC. After 87 h, the starting material was totally consumed
according to TLC. 2-Propanol (4 mL) was added to quench
the reaction and the resulting suspension was filtered. The
filtrate was concentrated to half of its original volume and
extracted with CH2Cl2 (2 · 32 mL). The combined organic
layers were dried over anhydrous Na2SO4, filtered and con-
centrated under vacuum. Silica gel column purification re-
sulted in the product (S)-1a (57 mg, 0.31 mmol, isolated
yield 77%, mp 65–66 ꢁC, ee(S)-1a = 99%).
Acknowledgement
This work was supported by the Academy of Finland
(Grant 109743 to L.K.).
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Deziel, R. J. Med. Chem. 1998, 41, 2882–2891.
´
2. Singh, G. S. Mini-Rev. Med. Chem. 2004, 4, 69–92.
3. Singh, G. S. Mini-Rev. Med. Chem. 2004, 4, 93–109.
4. Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Eur.
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5. Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M.
Synlett 2001, 1813–1826.
6. Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. In
Enantioselective Synthesis of b-Amino Acids, 2nd ed.; Juaristi,
E., Soloshonok, V., Eds.; Wiley-VHC: New York, 2005; pp
477–495.
7. Benaglia, M.; Cinquini, M.; Cozzi, F. Eur. J. Org. Chem.
2000, 563–572.
Using a similar procedure the enantiomers of other N-
hydroxymethylated b-lactams 2 were transformed in 87 h
into (R)-1a (isolated yield 75%, mp 66–69 ꢁC, ee(R)-1a
=
99%), in 125 h into (3R,4R)-1b (isolated yield 84%,
ee(3S,4S)-1b = 99%), in 120 h into (3S,4S)-1b (isolated yield
80%, ee(3S,4S)-1b = 99%) and in 120 h (2 ꢁC) followed by
an additional 48 h (room temperature) into both (R)-1 c
(isolated yield 20%, mp 106–107 ꢁC, ee(R)-1c = 99%) and
8. Uoto, K.; Ohsuki, S.; Takenoshita, H.; Ishiyama, T.; Iimura,
S.; Hirota, Y.; Mitsui, I.; Terasawa, H.; Soga, T. Chem.
Pharm. Bull. 1997, 45, 1793–1804.
9. Liljeblad, A.; Kanerva, L. T. Tetrahedron 2006, 62, 5831–
5854.
Table 3. Specific rotations for the prepared enantiomer pairs
22
Compound
ee (%)
½aꢁD (10ꢀ1 deg cm2 gꢀ1
)
(R)-1a
(S)-1a
(3R,4R)-1b
(3S,4S)-1b
(R)-1ca
(S)-1ca
99
99
99
99
99
99
99
99
99
99
99
99
ꢀ76.1 (c 1.00, CHCl3)
+76.3 (c 1.00, CHCl3)
ꢀ19.3 (c 1.00, CHCl3)
+19.3 (c 1.00, CHCl3)
+141.0 (c 0.50, EtOH)
ꢀ140.5 (c 0.50, EtOH)
ꢀ139.4 (c 1.05, CHCl3)
+139.2 (c 1.00, CHCl3)
ꢀ64.2 (c 1.10, CHCl3)
+64.3 (c 1.10, CHCl3)
+171.0 (c 1.00, EtOH)
ꢀ171.2 (c 1.00, EtOH)
25
´
10. Forro, E.; Fulo¨p, F. Mini-Rev. Org. Chem. 2004, 1, 93–102.
¨
´
´
´
11. Forro, E.; Paal, T.; Tasnadi, G.; Fulo¨p, F. Adv. Synth. Catal.
¨
2006, 348, 917–923.
12. Li, X.-G.; La¨hitie, M.; Pa¨ivio¨, M.; Kanerva, L. T. Tetrahe-
dron: Asymmetry 2007, 18, 1567–1573.
13. Sundholm, O.; Kanerva, L. T. J. Chem. Soc., Perkin Trans. 1
1993, 2407–2410.
(R)-2a
(S)-2a
(3R,4R)-2b
(3S,4S)-2b
(R)-2cb
(S)-2cb
25
´
14. Forro, E.; Fulo¨p, F. Tetrahedron: Asymmetry 2001, 12, 2351–
¨
2358.
15. Li, X.-G.; Kanerva, L. T. Adv. Synth. Catal. 2006, 348, 197–
205.
16. Georg, G. I.; Kant, J.; He, P.; Ly, A. M.; Lampe, L.
Tetrahedron Lett. 1988, 29, 2409–2412.
17. Lou, J.-D.; Zhu, L.-Y.; Wang, L.-Z. Monatsh. Chem. 2004,
135, 31–34.
a
½aꢁD ¼ þ132:4 (c 0.5, EtOH) for (R)-1c (ee = 97%) and ½aꢁD ¼ ꢀ136:3 (c
0.5, EtOH) for (S)-1c (ee = 99%); Ref. 14.
25
25
b
½aꢁD ¼ þ161 (c 0.35, EtOH) for (R)-2c (ee = 96%) and ½aꢁD ¼ ꢀ166:7 (c
1, EtOH) for (S)-2c (ee = 97%); Ref. 14.