Synthesis of enantiomerically pure 2-isoxacephems

Article abstract of DOI:10.1007/s00706-003-0135-9

(αR,6R,7R)-7-(1-Acetoxyethyl)-3-methyl-2-isoxacephem-4-carboxylic acid and its enantiomer have been prepared. The ring systems were formed from the corresponding enantiomerically pure N-unsubstituted β-lactams. The reduction of methyl [(αR,2S,3R)-3-(1-ace

Full text of DOI:10.1007/s00706-003-0135-9

Monatshefte f€ur Chemie 135, 671–684 (2004)
DOI 10.1007/s00706-003-0135-9
Synthesis of Enantiomerically Pure
2-Isoxacephems
1
1
2
´
Zsuzsanna Santa , Jozsef Nagy , Laszlo Parkanyi ,
and Jozsef Nyitrai
´
´
´
´
´
1;ꢀ
´
1
Institute for Organic Chemistry, Budapest University of Technology and
Economics, H-1521 Budapest, P.O. Box 91, Hungary
2
Institute of Chemistry, Chemical Research Center of Hungarian Academy
of Sciences, H-1525 Budapest, Hungary
Received September 30, 2003; accepted October 30, 2003
Published online February 5, 2004 # Springer-Verlag 2004
Summary. (ꢀR,6R,7R)-7-(1-Acetoxyethyl)-3-methyl-2-isoxacephem-4-carboxylic acid and its enantio-
mer have been prepared. The ring systems were formed from the corresponding enantiomerically pure
N-unsubstituted ꢁ-lactams. The reduction of methyl [(ꢀR,2S,3R)-3-(1-acetoxyethyl)-1-(4-me-
thoxyphenyl)-4-oxoazetidine-2-carboxylate] has been solved via a hemi-acetal. The structure and
the configuration of a new stereogenic center in this intermediate was predicted by using 2D NMR
technique and unambiguously proven by x-ray.
Keywords. Antibiotics; ꢁ-Lactams; Chiral building block; Enantioselectivity.
Introduction
Mono- and bicyclic ꢁ-lactams play a distinctive role in the therapy of bacterial
infections [1]. After the discovery of penicillins and cephalosporins, interest turned
to their nuclear analogues, such as carbapenems, oxacephems, and 2-isocephems
[2]. The research activity is still high owing to the growing number of resistant
strains of bacteria [3]. An excellent review was published in the late nineties
showing the growing spectra of resistant bacteria and the broad variations of their
resistance mechanism [4]. The first carbapenem, thienamycin 1a and its formami-
dine derivative 1b have been a great breakthrough in the antibacterial chemother-
apy for years owing to their broad spectra and ꢁ-lactamase stability due to the
2-hydroxyethyl side chain.
The more stable 1b is used under the trade name Imipenem with cilastatin
sodium, which prevents renal metabolism of penem and carbapenem antibiotics
ꢀ
Corresponding author. E-mail: nyitrai@mail.bme.hu

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Z. Santa et al.
672
Fig. 1. Thienamycin (1a) and its formamidine 1b
Scheme 1
by specific and reversible dehydropeptidase I inhibition. It makes thienamycin a
very expensive agent.
Among the 2-isoxa- and 2-isocephems some exhibited rather high antibacterial
activity [5]. Now, we decided to introduce the 1-hydroxyethyl group with proper
stereochemistry into position 7 of the 2-isoxacephem structure as shown in com-
pound 2. The retrosynthetic analysis of 2 shown in Scheme 1 led us to D-allo-
threonine as a chiral building block for the total synthesis of the target compound
2. The synthetic methods leading to 2-isoxacephems have been worked out by
using the cheapest threonine (L) and extended to the D-series. So, we have used
these amino acids first in order to see, whether our synthetic pathway is feasible or
not.
Results and Discussion
In recent papers we have described the stereoselective synthesis of monocyclic ꢁ-
lactams [6, 7] which has unambiguously shown the possibility of preparation of the
target trans-2-isoxacephems with optional stereochemistry. Before starting with the
properly substituted monocyclic compounds, the scope and limitation of two meth-
ods leading to 2-isoxacephems have been studied. We first report the extension and
comparison of these methods starting from 3 and 4 as model compounds (Scheme
2) in order to find the most effective route (for further examples see Ref. [8]).

Synthesis of Enantiomerically Pure 2-Isoxacephems
673
Scheme 2
Compound 3 is unsubstituted in position 3; compound 4 and the molecule to be
synthesized have sterically very similar substituents.
The first procedure (Method A) developed by us starts with the reaction of N-
unsubstituted ꢁ-lactams with benzyl 2,3-dioxobutyrate 5 [9] and the adducts are
converted without isolation into the corresponding 2-(2-oxo-3,4-disubstituted-
azetidin-1-yl)acetoacetates 6a and 7a. The second method (Method B) was
described by Durst [10]. It is based on an intermolecular carbene (generated from
the corresponding diazo ester 8) insertion reaction into the ꢁ-lactam N–H group
providing the acetoacetates 6b and 7b. In both methods cyclizations are carried out
with triethylamine in chloroform (9a, 10a, 9b, 10b). In all cases, the ‘‘dioxobuty-
rate’’ method gave better yields than the carbene insertion one.
A benzyl group was used in the ‘‘dioxobutyrate’’ method, a tert-butyl group in
the carbene insertion method as carboxyl protecting group. According to our earlier
results the tert-butyl ester protecting group can be removed easily by using AlCl3
in anisole [11] but the yields depend very much on substituents in position 7.
Benzyl and allyl protecting groups cannot be used in carbene insertion reactions
[12]. Similarly to other carbene insertion reactions, they are also very substrate
Scheme 3. i: A R ¼ benzyl: a) 5, Et3N=THF=rt, b) SOCl2=Py=THF=ꢁ25ꢂC, c) Zn=AcOH=4ꢂC; B
(R ¼ tert-butyl): 6 equiv. 8, 5 mol-% Rh2(OAc)4=benzene=reflux; ii: CHCl3=Et3N=reflux

´
Z. Santa et al.
674
Table 1. Overall yields of the products 9 and 10
Starting materials
Method A
R ¼ Bn
Method B
R ¼ t-Bu
3 R1 ¼ R2 ¼ H; Z ¼ Ts
4 R1 ¼ i-Pr; R2 ¼ H; Z ¼ Ms
Product
Yield
Product
Yield
9a
42%
46%
9b
25%
10%
10a
10b
dependent in our cases as well. In model compounds containing a 3-acylamino
group in monocyclic ꢁ-lactams the yields are satisfactory or good [10, 11] but in
the reactions of the compounds studied in this paper they are rather low. We think
that the Rh2(OAc)4 catalyst must form a complex with the ꢁ-lactam substrate and
with the diazoacetoacetate, which brings the carbene close to the ꢁ-lactam N–H
Scheme 4. i: mesyl chloride=Py=0–25ꢂC; ii: ammonium cerium(IV) nitrate=acetonitrile=water=
0ꢂC; iii: a) Et3N=THF=25ꢂC, b) SOCl2=Py=ꢁ25ꢂC, c) Zn=AcOH=4ꢂC; iv: Et3N=CHCl3=reflux;
v: H2=10% Pd=C=EtOAc

Synthesis of Enantiomerically Pure 2-Isoxacephems
675
group. Changing the catalyst from Rh to Cu will not improve the results, because
O-alkylation will be preferred instead of carbene insertion into the N–H bond in
case of lactams [13]. In spite of these results the carbene insertion reaction has
been tried on compound 14a as well, but the expected enol ester could not be
detected.
These preliminary experiences have convinced us about the only suitable way,
which might provide the target compounds 17a and 17b with satisfactory yield and
excellent optical purity. We have already proven the absolute configuration in
compound 12a (ꢀR,2S,3R), which determines the absolute configuration in com-
pound 11a (ꢀR,3R,4R) [7]. The following steps towards the target product 17a do
not affect the stereogenic centers, which means that the ‘‘dioxobutyrate’’-method
furnishes the enantiomerically pure benzyl ester that after hydrogenolyses provides
the (ꢀR,6R,7R)-7-(2-acetoxyethyl)-3-methyl-2-isoxacephem-4-carboxylic acid
(17a). Similarly, starting from D-threonine the enantiomer 2-isoxacephem-4-car-
boxylic acid (17b) could be obtained.
The reduction of cis-esters 12a and 12b should be solved in order to prepare
cis-annelated-2-isoxacephems. The ester 12a was used for preliminary investiga-
tions. In the first experiments di(isobutyl)aluminum hydride in toluene or THF was
chosen as reduction agent. The reactions were carried out at ꢁ78ꢂC. Two products
Scheme 5. i: DIBAL=THF=ꢁ78ꢂC; ii: 1 N HCl=reflux; iii: a) ClCOOEt=Et3N=THF=ꢁ20ꢂC, b)
NaBH4=MeOH=ꢁ20ꢂC; iv: NaBH4=MeOH=rt

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Z. Santa et al.
676
Scheme 6
were formed in low yield, a bicyclic lactone 18a and a bicyclic hemi-acetal 19a.
The reduction of 19a with sodium borohydride provided the cis-diol 20a in very
good yield. The ester 12a could be hydrolyzed with diluted hydrochloric acid at
surprisingly high temperature to the hydroxyacid 21a in good yield without
destroying the ꢁ-lactam ring. The reduction of 21a provided the hemi-acetal 19a
in excellent yield by using the mixed anhydride method [14]. Although 19a has a
new stereogenic center, it proved to be diastereomerically pure according its NMR
spectra.
The dihedral angle of hydrogen atoms in position 4 and 5 of 19a is approxi-
1
mately 90ꢂ. That is the reason, why there is no coupling between them in the H
NMR spectrum. Knowing the absolute configuration in position 5 (S), the absolute
configuration in position 4 must be (S). Compound 19a was O-acylated by 4-
bromobenzoyl chloride and the product 22a crystallized from dichloromethane.
Its Ortep plot is depicted in Fig. 2 showing that our prediction has been correct.
Fig. 2. Molecular structure of 22a; atomic displacement ellipsoids represent 50% probabilities

Synthesis of Enantiomerically Pure 2-Isoxacephems
677
Conclusion
Starting with building block threonine all stereoisomers of 2-isoxacephem can be
prepared in principle by stereoselective reactions. Two of the isomers (17a and
17b) have been successfully synthesized and the route leading to cis-annelated 2-
isoxacephems has also been opened.
Experimental
Melting points were determined on a hot stage melting point apparatus and are uncorrected. Optical
rotations (c¼ 1.0 g=100 cm3, CH2Cl2) were taken on a Perkin-Elmer 241 polarimeter, that was cali-
1
brated by measuring the optical rotations of both enantiomers of menthol. The H and 13C NMR
spectra were obtained using a Bruker DRX 500 spectrometer (1H 500.33 MHz, 13C 125.75 MHz) at
298 K in CDCl3 as solvent, unless stated otherwise. The IR spectra were recorded on a Specord M80
spectrophotometer. Mass spectra were measured with a Fisons Trio 1000 spectrometer at 70 eV, unless
stated otherwise. Elemental analyses (C, H, N, S) were conducted using the Elemental Analyser
VARIO EL III (Elementar Analysensysteme Gmbh), their results were found to be in good agreement
(ꢃ0.2%) with the calculated values. Column and thin-layer chromatography were carried out on
Merck Kieselgel 60 (0.063–0.2mm) and Merck Kieselgel 60 F254 Alufolien, respectively. For pre-
parative TLC Merck PSC ready-for-use plates (Kieselgel 60 F254, 20 ꢄ 20cm, 2 mm) were used. TLC
spots were detected by UV, and=or phosphomolybdenic acid (PMA). All of the known compounds (9a
[11], 9b [11], 10a [9]) were identified by their spectra. They are given in the experimental part, if the
resolution of their NMR spectra is higher, than those in the earlier papers.
Method A
N-Unsubstituted ꢁ-lactams 3–4 (10.0 mmol) and benzyl 2,3-dioxobutyrate 5 [9] (11.0mmol) were
dissolved in 100 cm3 of THF containing triethylamine (0.14 cm3). This solution was stirred at ambient
temperature until the starting material had practically disappeared (0.5h). The solution was cooled to
ꢁ25ꢂC and pyridine (1.33 cm3, 13.0mmol) was added to the mixture. Thionyl chloride (0.9cm3,
12.5mmol) in THF (30 cm3) was added dropwise at the same temperature and the mixture was stirred
for 1 h. It was allowed to warm up to room temperature, and the insoluble material was removed by
filtration. The solution was evaporated to dryness and the residue was taken up in a mixture of acetic
acid (200 cm3) and water (30 cm3). This solution was cooled to 4ꢂC and stirred with Zn powder (3.3g)
for 1 h. Inorganic material was filtered off, and the filtrate was concentrated in vacuum to dryness. The
residue was taken up in a mixture of CH2Cl2 and water (160cm3 each). The organic layer was
separated, dried (MgSO4), and the solution was concentrated to give an oily crude product as a mixture
of 6a and 7a (TLC, n-hexane:ethyl acetate ¼ 6:5, Rf(6a): 0.3, Rf(7a): 0.5). This crude product was
dissolved in 60 cm3 of CHCl3 and was refluxed in the presence of Et3N (2.0cm3, 14.4 mmol) for 2 h.
The concentrated solution was purified by column chromatography (R1 ¼ H or i-Pr, n-hexane:ethyl
acetate ¼ 10:0.1! 10:2, TLC: n-hexane:ethyl acetate ¼ 6:5, Rf(9a): 0.6, Rf(10a): 0.8). Fractions with
appropriate Rf values were collected and evaporated to give 9a (42%) and 10a (46%).
Method B
N-Unsubstituted ꢁ-lactams 3–4 (10.0mmol) were dissolved in hot benzene (75 cm3) and rhodium
acetate (0.5mmol) was added to this mixture. This solution was heated to reflux temperature. t-Butyl
2-diazo-3-oxobutyrate 8 (60.0 mmol) was dissolved in 30cm3 of benzene and this solution was
dropped into the reaction mixture. The solution was cooled to room temperature after 30min refluxing.
Rhodium acetate was filtered off, and the filtrate was clarified with charcoal, and concentrated in

´
Z. Santa et al.
678
vacuum. The residue was purified by column chromatography (R1 ¼ H or i-Pr, n-hexane:ethyl ace-
tate¼ 10:0.1! 1:1, TLC: n-hexane:ethyl acetate ¼ 6:5, Rf(6b): 0.3, Rf(7b): 0.4. The oily product was
refluxed in CHCl3 (25 cm3) in the presence of Et3N (1.4 eq.) for 2 h. The solution was concentrated to
dryness and the crude product was purified by column chromatography (R1 ¼ H or i-Pr, n-hexane:ethyl
acetate ¼ 10:0.1! 1:1, TLC: n-hexane:ethyl acetate ¼ 6:5, Rf(9b): 0.6, Rf(10b): 0.8) to give 9b (25%),
10b (10%).
tert-Butyl (þ=ꢁ)-3-Methyl-2-isoxacephem-4-carboxylate
(9b, C12H17NO4, R1 ¼ R2 ¼ H, R ¼ t-Bu) [11]
1
Mp 94–96ꢂC (ethyl acetate); IR (KBr): ꢂꢀ¼ 3000, 1760, 1690, 1210, 1100, 1050 cmꢁ1; H NMR
(500 MHz): ꢃ ¼ 1.54 (s, C(CH3)3), 2.22 (s, 3-CH3), 2.63 and 3.45 (ABX, Jgem ¼ 15.2, Jtrans,H6 ¼ 1.9,
Jcis,H6 ¼ 4.8Hz, 7-CH2), 3.53 (dddd, Jtrans;H7 ¼ 1.9, Jcis;H7 ¼ 4.8, JH6;1ꢁCH ¼ 9.5 and 3.2Hz, H6),
A
B
2
3.59 and 4.62 (ABX, Jgem ¼ 10.0, J1ꢁCH ;H6 ¼ 9.5 and 3.2 Hz, 1-CH2) ppm.
2
Benzyl ðþ=ꢁÞ-trans-7-Isopropyl-3-methyl-2-isoxacephem-4-carboxylate
(10a, C17H19NO4, R1 ¼ i-Pr, R2 ¼ H, R ¼ Bn) [9]
Mp 78ꢂC (diisopropyl ether); IR (KBr): ꢂꢀ¼ 1770, 1700 (CO) cmꢁ1; 1H NMR (500MHz): ꢃ ¼ 1.03 and
1.10 (2d, Jvic ¼ 6.6 Hz, CH(CH3)2), 2.19 (m, Jvic ¼ 6.6, JHꢀ,H7 ¼ 7.5 Hz, CH(CH3)2), 2.23 (s, 3-CH3),
2.64 (dd, JH7,Hꢀ ¼ 7.5, Jtrans,H6 ¼ 2.0 Hz, H7), 3.27 (ddd, JH6;1ꢁCH ¼ 9.5 and 3.5, Jtrans,H7 ¼ 2.0 Hz,
2
H6), 3.64 (dd, Jgem ¼ 10.5, JH1
¼ 9.5 Hz, H1 ), 4.60 (dd, J ¼ 10.5, JH1 ;H6 ¼ 3.5 Hz, H1 ), 5.28
A;H6
A
gem
B
B
(s, CH2Ph), 7.25–7.55 (m, 5 ArH) ppm.
tert-Butyl ðþ=ꢁÞ-trans-7-Isopropyl-3-methyl-2-isoxacephem-4-carboxylate
(10b, C15H23NO4, R1 ¼ i-Pr, R2 ¼ H, R ¼ t-Bu)
1
Mp 82–85ꢂC (ethyl acetate); IR (KBr): ꢂꢀ¼ 2990, 2972, 1760, 1720, 1250, 1050 cmꢁ1; H NMR
(500 MHz): ꢃ ¼ 1.04 and 1.10 (2d, Jvic ¼ 7 Hz, CH(CH3)2), 1.53 (s, C(CH3)3), 2.17 [m, JHꢀ,H7 ¼ 7.5,
Jvic ¼ 7 Hz, CH(CH3)2], 2.19 (s, 3-CH3), 2.64 (dd, JHꢀ,H7 ¼ 7.5, Jtrans,H6 ¼ 1.9 Hz, H7), 3.27 (ddd,
JH6;1-CH ¼ 10.0 and 3.6, Jtrans,7-H ¼ 1.9 Hz, H6), 3.59 (dd, Jgem ¼ 10.0, JH1
¼ 10.0 Hz, 1H, H1 ),
A;H6
A
2
4.58 (dd, Jgem ¼ 10.0, JH1 ;H6 ¼ 3.6 Hz, 1H, H1B) ppm.
B
(ꢀR, 3R, 4R)-3-(1-Acetoxyethyl)-4-hydroxymethyl-N-(4-methoxyphenyl)-azetidin-2-one
(11a, C15H19NO5)a
23:5
Oil; ½ꢀꢅd ¼ þ48:6ꢂ gꢁ1 cm3 dmꢁ1; IR (neat): ꢂꢀ¼ 3600–3200 (OH), 1740 (CON), 1710 (CO), 1230
1
and 1010 (COC) cmꢁ1; H NMR (500MHz): ꢃ ¼ 1.43 (d, JCH ;Hꢀ ¼ 6.5 Hz, ꢁ-CH3), 1.9 (brs, OH),
3
2.03 (s, CH3CO), 3.46 (dd, JH3,Hꢀ ¼ 4.6, Jtrans,H4 ¼ 2.5 Hz, H3), 3.79 (s, OCH3), 3.90 (dd, Jgem ¼ 12,
JCH
JCH
¼ 3.5 Hz, 1H, CH2AO), 3.98 (td, Jtrans,H3 ¼ 2.6, JH4;CH ¼ 3.6 Hz, 1H, H4), 4.02 (dd, Jgem ¼ 12,
2A;H4
2
¼ 3.75Hz, 1H, CH2BO), 5.31 (m, JHꢀ;CH ¼ 6.5, JHꢀ,H3 ¼ 4.6 Hz, Hꢀ), 6.89 (d, Jortho ¼ 9 Hz,
2B;H4
3
H30, H50), 7.35 (d, Jortho ¼ 9 Hz, H20, H60) ppm.
(ꢀR, 3R, 4R)-3-(1-Acetoxyethyl)-4-(mesyloxymethyl)-N-(4-methoxyphenyl)-
azetidin-2-one (13a, C16H21NO7S)
Mesyl chloride (1.2cm3, 12 mmol) was added under stirring and cooling (ꢁ5–0ꢂC) to compound 11a
(3.0g, 10mmol) dissolved in pyridine (20 cm3). The stirring was continued for 2.5 h (TLC:
a
The stereodescriptors given in Ref. [7] for compound 11a are wrong

Synthesis of Enantiomerically Pure 2-Isoxacephems
679
CH2Cl2:EtOAc¼ 8:5, Rf(11a): 0.5, Rf(13a): 0.6). The reaction mixture was diluted with water (20 cm3)
anddichloromethane(60 cm3).Theorganiclayerwaswashedwith10%HCl(3ꢄ 20 cm3),thenwithwater
(3ꢄ 20cm3). The solution was dried (MgSO4) and concentrated to dryness. The crude oil was purified by
column chromatography (CH2Cl2 ! CH2Cl2:EtOAc¼ 10:1) to give the title compound (2.9g, 76%).
20
Brownish oil; ½ꢀꢅd ¼ þ57:6ꢂ gꢁ1 cm3 dmꢁ1; IR (neat): ꢂꢀ¼ 1740 (CON), 1710 (CO), 1516, 1360 and
1176 (SO2), 1240 and 1028 (COC) cmꢁ1; 1H NMR (500MHz): ꢃ ¼ 1.43 (d, JCH ;Hꢀ ¼ 7.0 Hz, ꢁ-CH3),
3
2.04 (s, CH3CO), 2.92 (s, SO2CH3), 3.46 (dd, JH3,Hꢀ ¼ 4.0, Jtrans,H4 ¼ 2.0 Hz, H3), 3.79 (s, OCH3), 4.17
(m, H4), 4.51 (d, JCH O;H4 ¼ 4.5 Hz, CH2O), 5.32 (m, Hꢀ), 6.89 (d, Jortho ¼ 8.8 Hz, H30, H50), 7.32 (d,
2
Jortho ¼ 8.8 Hz, H20, H60) ppm; 13C NMR (125 MHz): ꢃ ¼ 18.22 (ꢁ-CH3), 21.81 (CH3CO), 38.26
(SO2CH3), 52.75, 56.12, 57.12, 67.18, and 67.62 (Cꢀ, C3, C4, CH2O, CH3O), 115.12 (C30, C50),
119.26 (C20, C60), 130.27 (C10), 157.02 (C40), 162.95 (CON), 170.70 (CH3CO) ppm; MS: m=z
(%) ¼ 371 (Mþ, 23), 311 (13), 243 (13), 202 (17), 149 (100), 134 (82), 43 (61).
(ꢀS, 3S, 4S)-3-(1-Acetoxyethyl)-4-(mesyloxymethyl)-N-(4-methoxyphenyl)-
azetidin-2-one (13b, C16H21NO7S)
22:5
Prepared analogously as 13a. Yield: 75%; ½ꢀꢅd ¼ ꢁ51:7ꢂ gꢁ1 cm3 dmꢁ1; IR (neat): ꢂꢀ¼ 1740 (CON),
1516, 1366, and 1176 (SO2), 1248 and 1028 (COC) cmꢁ1
;
1H NMR (500 MHz): ꢃ ¼ 1.45 (d,
JCH ;Hꢀ ¼ 6.6 Hz, ꢁ-CH3), 2.06 (s, CH3CO), 2.93 (s, SO2CH3), 3.47 (dd, JH3,Hꢀ ¼ 4.3, Jtrans,H4 ¼ 2.4 Hz,
3
H3), 3.80 (s, OCH3), 4.18 (m, H4), 4.46 (d, JCH O;H4 ¼ 4.1 Hz, CH2O), 5.33 (m, Hꢀ), 6.90 (d,
2
Jortho ¼ 8.9 Hz, H30, H50), 7.32 (d, Jortho ¼ 9.0 Hz, H20, H60) ppm; 13C NMR (125MHz): ꢃ ¼ 18.22 (ꢁ-
CH3), 21.83 (CH3CO), 38.29 (SO2CH3), 52.75, 56.13, 57.16, 67.18, and 67.62 (C-ꢀ, C-3, C-4, CH2O,
CH3O), 115.12 (C30, C50), 119.25 (C20, C60), 130.33 (C10), 157.03 (C40), 162.92 (CON), 170.70
(CH3CO) ppm; MS: m=z (%) ¼ 371 (Mþ, 20), 311 (13), 243 (13), 202 (15), 149 (100), 134 (85), 43 (62).
(ꢀR, 3R, 4R)-3-(1-Acetoxyethyl)-4-(mesyloxymethyl)azetidin-2-one
(14a, C9H15NO6S)
Ammonium cerium(IV) nitrate (11 g, 20 mmol) dissolved in water (120cm3) was added to the solution
of compound 13a (2.5g, 6.7 mmol) in acetonitrile (70 cm3) under cooling (ꢁ10–0ꢂC) and stirring. The
starting material was consumed after 2 h (TLC: CH2Cl2:EtOAc¼ 1:1, Rf(13a): 0.5, Rf(14a): 0.15).
The reaction mixture was diluted with water (200cm3) and extracted with EtOAc (3ꢄ 150 cm3). The
combined organic layers were washed with 10% NaHCO3 solution (85 cm3), then the aqueous layer
was extracted with EtOAc (40 cm3). The combined organic layers were washed with 10% NaHSO3
solutions until they became colorless and the aqueous layer was extracted with EtOAc. The combined
organic layers were washed with 10% Na2CO3 solutions, dried (Na2SO4), and concentrated to dryness.
The crude oil was purified by column chromatography (CH2Cl2 ! CH2Cl2:EtOAc¼ 1:1) to give the
22:5
title compound (1.30 g, 73%). Slowly crystallizing oil; mp 70ꢂC; ½ꢀꢅd ¼ ꢁ21:5ꢂ gꢁ1 cm3 dmꢁ1; IR
(KBr): ꢂꢀ¼ 3700–3400 (NH), 1750 and 1720 (CO), 1330 and 1160 (SO2), 1230 and 1020 (COC) cmꢁ1
;
1H NMR (500MHz): ꢃ ¼ 1.41 (d, JCH ;Hꢀ ¼ 6.45Hz, ꢁ-CH3), 2.08 (s, CH3CO), 3.08 (s, SO2CH3), 3.24
3
(m, H3), 3.81 (m, H4), 4.27 (dd, JCH
¼ 6.5, J ¼ 11Hz, 1H, CH2AO), 4.40 (dd, JCH
¼ 3.5,
2A;H4
2B;H4
gem
Jgem ¼ 11 Hz, 1H, CH2BO), 5.25 (qui, Jvic ¼ 6.2 Hz, Hꢀ), 6.14 (brs, NH) ppm; 13C NMR (125MHz):
ꢃ ¼ 17.39 (ꢁ-CH3), 21.15 (CH3CO), 37.80 (SO2CH3), 48.92, 57.66, 66.63, and 69.35 (Cꢀ, C3, C4,
CH2O), 165.64 (CON), 170.5 (CH3CO) ppm; MS (18 eV): m=z (%) ¼ 266 (MþþH, 0.7), 222 (0.7),
113 (37), 84 (100), 43 (92).
(ꢀS, 3S, 4S)-3-(1-Acetoxyethyl)-4-(mesyloxymethyl)azetidin-2-one (14b, C9H15NO6S)
24
Prepared analogously as 14a. Yield: 75%; mp 72ꢂC; ½ꢀꢅd ¼ þ20:5ꢂ gꢁ1 cm3 dmꢁ1; IR (KBr):
1
ꢂꢀ¼ 3500–3300 (NH), 1760 and 1740 (CO), 1356 and 1176 (SO2), 1244 and 1028 (COC) cmꢁ1; H

´
Z. Santa et al.
680
NMR (500 MHz): ꢃ ¼ 1.41 (d, JCH ;Hꢀ ¼ 6.5 Hz, ꢁ-CH3), 2.09 (s, CH3CO), 3.09 (s, SO2CH3), 3.25 (dd,
3
JH3,Hꢀ ¼ 3.6, Jtrans,H4 ¼ 2.6 Hz, H3), 3.81 (ABX, H4), 4.28 (ABX, JCH
¼ 6.5, J ¼ 10.9 Hz, 1H,
3
2A;H4
gem
CH2AO), 4.41 (ABX, JCH
¼ 3.7, J ¼ 10.9Hz, 1H, CH2BO), 5.25 (qd, JHꢀ;CH ¼ 6.4,
2B;4-H
gem
JHꢀ,H3 ¼ 4.6 Hz, Hꢀ), 6.43 (brs, NH) ppm; 13C NMR (125MHz): ꢃ ¼ 18.11 (ꢁ-CH3), 21.85 (CH3CO),
38.38 (SO2CH3), 49.49, 58.17, 67.23, and 70.03 (Cꢀ, C3, C4, CH2O), 166.24 (CON), 170.72 (CH3CO)
ppm; MS (18 eV): m=z (%) ¼ 266 (MþþH, 0.7), 222 (0.7), 113 (36), 84 (100), 43 (93).
Benzyl (ꢀR, 6R, 7R)-7-(1-Acetoxyethyl)-3-methyl-2-isoxacephem-4-
carboxylate (16a, C19H21NO6)
Compound 16a was prepared according to Method A starting with 14a (1.25 g, 4.7 mmol) and benzyl
2,3-dioxobutyrate [9] (1.5g, 7 mmol). The oily crude intermediate (2.5g) (TLC:
CH2Cl2:EtOAc¼ 10:2, Rf(14a): 0.05 PMA, Rf(15a): 0.35) was purified by column chromatography
(CH2Cl2 ! CH2Cl2:EtOAc¼ 1:1) provided 15a (1.0g, 47%) and the starting material 11a (0.4g, 32%).
Crude 15a (0.9g, 2 mmol) was dissolved in CHCl3 (15 cm3) and in the presence of Et3N (0.1cm3,
7.2 mmol) it was refluxed for 1 h (TLC: CH2Cl2:EtOAc¼ 10:2, Rf(16a): 0.5). The concentrated
solution was washed with water and purified by column chromatography (CH2Cl2 ! CH2Cl2:
22
EtOAc¼ 10:2) to give the title compound 16a (0.38 g, 53%). Colorless oil; ½ꢀꢅd
¼
ꢁ121:0ꢂ gꢁ1 cm3 dmꢁ1; IR (film): ꢂꢀ¼ 1770, 1744 and 1710 (CO), 1616 (Ar), 1456, 1376, 1240,
1
1136, 1084 and 1028 (COC) cmꢁ1; H NMR (500MHz): ꢃ ¼ 1.42 (d, JCH ;Hꢀ ¼ 6.5 Hz, ꢁ-CH3),
3
1.99 (s, CH3CO), 2.24 (s, 3-CH3), 3.09 (dd, Jtrans,H6 ¼ 1.8, JH7,Hꢀ ¼ 4 Hz, H7), 3.39 (ddd,
Jtrans,H7 ¼ 1.8, JH6;H1 ¼ 9.4, JH6;H1 ¼ 3 Hz, H6), 3.67 (t, J ¼ 10.0 Hz, 1H, H1A), 4.64 (dd,
A
B
JH1 ;H6 ¼ 3.7, Jgem ¼ 10.7Hz, 1H, H1B), 5.23þ 5.30 (AB, Jgem ¼ 12.7Hz, ArCH2), 5.33 (qd,
B
JHꢀ,H7 ¼ 4.3, JHꢀ;CH ¼ 6.5 Hz, Hꢀ), 7.29 (t, Jortho ¼ 7.5 Hz, H40), 7.34 (t, Jortho ¼ 7.3 Hz, H30, H50),
3
7.44 (d, Jortho ¼ 7.4 Hz, H20, H60) ppm; 13C NMR (125MHz): ꢃ ¼ 17.76 (3-CH3, ꢁ-CH3), 21.06
(CH3CO), 43.60 (C6), 60.69 (C7), 66.55 and 66.76 (Cꢀ, ArCH2), 69.27 (C1), 106.69 (C4), 127.94,
127.97, 128.38, and 136.07 (Ar–C), 154.53 (C3), 162.94 and 164.18 (CON, COOCH2), 170.47
(CH3CO) ppm; MS: m=z (%) ¼ 359 (Mþ, 8), 317 (6), 226 (8), 125 (6), 91 (100), 43 (55).
Benzyl (ꢀS, 6S, 7S)-7-(1-Acetoxyethyl)-3-methyl-2-isoxacephem-4-carboxylate
(16b, C19H21NO6)
20:5
Prepared analogously as 16a. Yield: 28%; oil; ½ꢀꢅd ¼ þ130:0ꢂ gꢁ1 cm3 dmꢁ1; IR (film): ꢂꢀ¼ 1780,
1
1736, 1720 (CO), 1620 (Ar), 1456, 1392, 1375, 1355, 1240, 1136, 1084 and 1028 (COC) cmꢁ1; H
NMR (500MHz): ꢃ ¼ 1.45 (d, JCH ;Hꢀ ¼ 6.5 Hz, ꢁ-CH3), 2.02 (s, CH3CO), 2.26 (s, 3-CH3), 3.12 (dd,
3
Jtrans,H6 ¼ 1.8, JH7,Hꢀ ¼ 4 Hz, H7), 3.42 (ddd, Jtrans,H7 ¼ 1.8, JH6;H1 ¼ 9.4, JH6;H1 ¼ 3.5 Hz, H6), 3.69
A
B
(t, J ¼ 9.7 Hz, 1H, H1A), 4.66 (dd, JH1 ;H6 ¼ 3.7, Jgem ¼ 10.7Hz, 1H, H1B), 5.25þ 5.31 (AB,
B
Jgem ¼ 12.6 Hz, ArCH2), 5.33 (qd, JHꢀ,H7 ¼ 4.3, JHꢀ;CH ¼ 6.5 Hz, Hꢀ), 7.31 (t, Jortho ¼ 7.3 Hz, H40),
3
7.36 (t, Jortho ¼ 7.3 Hz, H30, H50), 7.46 (d, Jortho ¼ 7.3 Hz, H20, H60) ppm; 13C NMR (125MHz):
ꢃ ¼ 18.48 (3-CH3, ꢁ-CH3), 21.76 (CH3CO), 44.24 (C6), 61.29 (C7), 67.13 and 67.32 (Cꢀ, ArCH2),
69.83 (C1), 107.16 (C4), 128.34, 128.37, 128.77, and 136.43 (Ar–C), 154.84 (C3), 163.21, 164.44
(CON, COOCH2), 170.74 (CH3CO) ppm.
(ꢀR, 6R, 7R)-7-(1-Acetoxyethyl)-3-methyl-2-isoxacephem-4-carboxylic acid
(17a, C12H15NO6)
The benzyl ester 16a (0.35 g, 0.97 mmol) was hydrogenated in ethyl acetate (15 cm3) in the presence of
10% Pd=C catalyst (0.05 g) under atmospheric pressure for 2 h (TLC: CH2Cl2:EtOAc¼ 10:2, Rf(17a):
0.1; CH2Cl2:MeOH ¼ 10:1, Rf(17a): 0.3). The catalyst was filtered off, washed with ethyl acetate and
24:5
concentrated to dryness to give the title compound (0.24 g, 92%). Colorless oil; ½ꢀꢅd
¼

Synthesis of Enantiomerically Pure 2-Isoxacephems
681
ꢁ193:0ꢂ gꢁ1 cm3 dmꢁ1; IR (film): ꢂꢀ¼ 3000–3300 (COOH), 1780 and 1736 (CO), 1612 (Ar), 1244 and
1028 (COC) cmꢁ1; 1H NMR (500MHz): ꢃ ¼ 1.44 (d, JCH ;Hꢀ ¼ 6.5 Hz, ꢁ-CH3), 2.09 (s, CH3CO), 2.29
3
(s, 3-CH3), 3.19 (dd, Jtrans,H6 ¼ 2.0, JH7,Hꢀ ¼ 4.0 Hz, H7), 3.49 (ddd, Jtrans,H7 ¼ 2.0, JH6;H1 ¼ 7.5,
A
JH6;H1 ¼ 3.0 Hz, H6), 3.73 (t, J ¼ 10.0 Hz, 1H, H1A), 4.69 (dd, JH1 ;H6 ¼ 3.7, Jgem ¼ 10.7 Hz, 1H,
B
B
H1B), 5.32 (qd, JHꢀ,H7 ¼ 4.3, JHꢀ;CH ¼ 6.5 Hz, Hꢀ) ppm; 13C NMR (125MHz): ꢃ ¼ 17.78 (ꢁ-CH3),
3
18.06 (3-CH3), 21.18 (CH3CO), 44.35 (C6), 60.07 (C7), 66.59 (Cꢀ), 69.09 (C1), 106.54 (C4), 156.54
(C3), 165.05 (COOH), 165.47 (CON), 170.60 (CH3CO) ppm; MS: m=z (%) ¼ 269 (Mþ, 3), 227 (8),
183 (6), 141 (6), 123 (5), 98 (10), 69 (9), 54 (9), 43 (100).
(ꢀS, 6S, 7S)-7-(1-Acetoxyethyl)-3-methyl-2-isoxacephem-4-carboxylic acid
(17b, C12H15NO6)
22:5
Prepared analogously as 17a. Yield: 28%; colorless oil; ½ꢀꢅd ¼ þ193:3ꢂ gꢁ1 cm3 dmꢁ1; IR (film):
1
ꢂꢀ¼ 3000–3300 (COOH), 1780, 1740, and 1725 (CO), 1608 (Ar), 1244 and 1028 (COC) cmꢁ1; H
NMR (500MHz): ꢃ ¼ 1.45 (d, JCH ;Hꢀ ¼ 6.5 Hz, ꢁ-CH3), 2.11 (s, CH3CO), 2.31 (s, 3-CH3), 3.20 (d,
3
Jtrans,H6 ¼ 2.0Hz, H7), 3.48 (d, JH6;H1 ¼ 7.5 Hz, H6), 3.74 (t, J ¼ 9.9 Hz, 1H, H1A), 4.70 (dd,
A
JH1 ;H6 ¼ 3.7, Jgem ¼ 10.7 Hz, 1H, H1B), 5.33 (qd, JHꢀ,H7 ¼ 4.4, JHꢀ;CH ¼ 6.5 Hz, Hꢀ), 9.22 (brs,
B
3
COOH) ppm; 13C NMR (125MHz): ꢃ ¼ 18.46 and 18.76 (ꢁ-CH3, 3-CH3), 21.88 (CH3CO), 44.94
(C6), 60.65 (C7), 67.14 (Cꢀ), 69.64 (C1), 106.99 (C4), 156.83 (C3), 165.52 and 165.65 (CON,
COOH), 170.82 (CH3CO) ppm; MS: m=z (%) ¼ 269 (Mþ, 3), 227 (7), 183 (6), 141 (6), 123 (5), 98
(9), 69 (9), 54 (9), 43 (100).
(1R, 2R, 5S)-6-(4-Methoxyphenyl)-2-methyl-3-oxa-6-azabicyclo[3.2.0]heptane-
4,7-dione (18a, C13H13NO4)
The cis-ester 12a (1.60 g, 5.0 mmol) was suspended in dry THF (25 cm3) and 1 M DIBAL in THF
(15.0cm3, 15.0mmol) was added under nitrogen at ꢁ70ꢂC in such a rate, that the temperature did not
rise above ꢁ65ꢂC. Stirring was continued for 2 h (TLC: CH2Cl2:EtOAc ¼ 10:2, Rf(12a): 0.70, Rf(18a):
0.50, Rf(19a): 0.20). A further amount of 1 M DIBAL in THF (7.0cm3, 7.0 mmol) was added under
nitrogen at ꢁ70ꢂC and after 0.5 h stirring the excess of the reagent was decomposed by addition of
methanol (5cm3). The mixture was allowed to warm up to rt, acidified by 10% HCl (50 cm3), and
extracted with ethyl acetate (2ꢄ 100 cm3). The combined organic phases were washed subsequently
with saturated NaHCO3 solution, water, and dried (MgSO4). The crude product (1.20 g) was purified
by column chromatography (CH2Cl2 ! CH2Cl2:EtOAc¼ 1:1) to give unreacted 12a (0.50 g, 31%), 19a
(0.24 g, 20%), and 18a (50.0 mg, 3%). Mp 145ꢂC (MeOH); IR (KBr): ꢂꢀ¼ 1744 (CO), 1516 (Ar), 1248
1
and 1044 (COC) cmꢁ1; H NMR (500 MHz): ꢃ ¼ 1.64 (d, JH2;CH ¼ 6.0 Hz, CH3), 3.79 (s, ArOCH3),
3
4.04 (dd, JH5,H1 ¼ 4.6, JH2,H1 ¼ 7.5 Hz, H1), 4.64 (d, JH1,H5 ¼ 4.7 Hz, H5), 4.83 (qui, J ¼ 6.8 Hz, H2),
6.88 (d, Jortho ¼ 8.9 Hz, H30, H50), 7.50 (d, Jortho ¼ 8.9 Hz, H20, H60) ppm; 13C NMR (125MHz):
ꢃ ¼ 18.18 (CH3), 53.96, 54.78, and 55.71 (CH3OAr, C1, C5), 75.26 (C2), 114.69 (C30, C50), 118.54
(C20, C60), 130.78 (C10), 156.99 (C40), 160.95 (CON), 170.62 (C4) ppm.
(1R, 2R, 4S, 5S)-4-Hydroxy-6-(4-methoxyphenyl)-2-methyl-3-oxa-6-azabicyclo
[3.2.0]heptan-7-one (19a, C13H15NO4)
Ethyl chloroformate (1.6cm3, 15.0mmol) dissolved in THF (6cm3) was added to the mixture of cis-
hydroxyacid 21a (1.94 g, 6.0 mmol) and triethylamine (2.2cm3, 15.0mmol) in THF (23 cm3) at ꢁ20ꢂC
under stirring. After consumption of the acid 21a (TLC: CH2Cl2:EtOAc¼ 10:2, Rf(21a): 0.10, Rf(an-
hydride): 0.50) NaBH4 (1.75 g, 46.0mmol) was added to the solution. A mixture of methanol (15cm3)
and THF (10 cm3) was dropped into the reaction mixture within 2 h at the same temperature. The
reaction was monitored by TLC (CH2Cl2:EtOAc¼ 10:2, Rf(19a): 0.10). The THF=MeOH solution was

´
Z. Santa et al.
682
concentrated to dryness, the residue was diluted with saturated NaCl solution (25 cm3), extracted with
EtOAc (2ꢄ 40 cm3), washed with brine, and dried (MgSO4). Evaporation provided an oily crude
product (1.80 g) which was purified by column chromatography (CH2Cl2 ! CH2Cl2:EtOAc ¼ 1:1) to
give besides 20a (8%), the ethoxyformyl derivative of 19a (10%), and the title compound (1.26 g,
21:5
84%). Mp 184ꢂC; ½ꢀꢅd ¼ ꢁ98:8ꢂ gꢁ1 cm3 dmꢁ1; IR (KBr): ꢂꢀ¼ 1720 (CO), 1516 (Ar), 1244 (COC),
1
968, 832 cmꢁ1; H NMR (500 MHz, DMSO-d6, COSY): ꢃ ¼ 1.35 (d, JH2;CH ¼ 6.5 Hz, CH3), 3.73 (s,
3
ArOCH3), 3.78 (dd, JH5,H1 ¼ 4.4, JH2,H1 ¼ 5.3 Hz, H1), 4.23 (qui, J ¼ 6.0 Hz, H2), 4.38 (d,
JH1,H5 ¼ 4.0 Hz, H5), 5.30 (d, JH4,OH ¼ 4.3 Hz, OH), 6.61 (d, JOH,H4 ¼ 4.3Hz, H4), 6.95 (d,
Jortho ¼ 8.9 Hz, H30, H50), 7.29 (d, Jortho ¼ 8.9 Hz, H20, H60) ppm; 13C NMR (125MHz, DMSO-d6):
15.66 (CH3), 55.28, 56.34, 61.19, and 69.71 (CH3OAr, C1, C5, C2), 94.03 (C4), 114.62 (C30, C50),
117.24 (C20, C60), 130.87 (C10), 155.50 (C40), 162.82 (CON) ppm.
(ꢀR, 3R, 4S)-3-(1-Hydroxyethyl)-4-(hydroxymethyl)-1-(4-methoxyphenyl)-
azetidin-2-one (20a, C13H17NO4)
Sodium borohydride (1.90 g, 50.0mmol) was added in small portions to the solution (MeOH, 150cm3)
of cyclic hemi-acetal 19a (3.10 g, 12.0mmol) at 0ꢂC under stirring. The reaction was monitored by
TLC (CH2Cl2:EtOAc¼ 1:1, Rf(19a): 0.5, Rf(20a): 0.2). The mixture was stirred 1 h at rt, concentrated
to dryness the residue was suspended in water (30 cm3), and it was acidified with 1 N HCl to pH ¼ 6.0.
The precipitated product was filtered off and proved to be the title compound 20a (2.40 g, 80%). A
second crop (0.80 g) could be isolated from the aqueous solution by extraction with EtOAc. This was
triturated with methanol to give 0.60g (20%) of 20a. Mp 198–201ꢂC; IR (KBr): ꢂꢀ¼ 3200, 3288 (OH),
1728 (CO), 1512 (Ar), 1248 and 1024 (COC), 832 cmꢁ1; 1H NMR (500 MHz, DMSO-d6): ꢃ ¼ 1.28 (d,
JHꢀ;CH ¼ 5.8 Hz, ꢁ-CH3), 3.4 (m, H3), 3.72 (s, ArOCH3), 3.88 þ 3.98 (AB, Jgem ¼ 9 Hz, CH2), 4.07
3
and 4.12 (2m, H4, Hꢀ), 5.03 and 5.15 (2brs, 2OH), 6.91 (d, Jortho ¼ 8.2 Hz, H30, H50), 7.46 (d,
Jortho ¼ 8.2 Hz, H20, H60) ppm; 13C NMR (125MHz, DMSO-d6): ꢃ ¼ 23.18 (ꢁ-CH3), 55.41, 56.90,
57.86, 59.12, and 62.61 (C3, C4, Cꢀ, CH2, ArOCH3), 114.31 (C30, C50), 118.38 (C20, C60), 131.96
(C10), 155.30 (C40), 165.66 (CON) ppm.
(ꢀR, 2S, 3R)-3-(1-Hydroxyethyl)-1-(4-methoxyphenyl)-4-oxoazetidine-2-
carboxylic acid (21a, C13H15NO5)
The cis-ester 12a (3.20 g, 10.0 mmol) was suspended in 1 N HCl (30 cm3) and the suspension was
refluxed for 20 h. The insoluble material was filtered off and triturated with CH2Cl2 (30 cm3) at rt. The
insoluble material was filtered off and proved to be 21a (2.0g, 77%). Unreacted 12a could be
recovered from the CH2Cl2 solution (0.1g, 3%).
21a: Mp 169ꢂC; IR (KBr): ꢂꢀ¼ 3368 (OH), 1736, 1712 (CO), 1512 (Ar), 1248 and 1024 (COC),
832 cmꢁ1
;
1H NMR (500 MHz, DMSO-d6): ꢃ ¼ 1.26 (d, JHꢀ;CH ¼ 6.4 Hz, ꢁ-CH3), 3.59 (dd,
3
JHꢀ,H3 ¼ 4.1, JH2,H3 ¼ 6.2 Hz, H3), 3.72 (s, ArOCH3), 4.02 (qd, JH3,Hꢀ ¼ 4.3, JCH ;Hꢀ ¼ 6.0 Hz, ꢀ-
3
H), 4.66 (d, JH3,H2 ¼ 6.4 Hz, H2), 4.85 (brs, OH), 6.91 (d, Jortho ¼ 8.9 Hz, H30, H50), 7.28 (d,
Jortho ¼ 8.8 Hz, H20, H60), 12.85 (brs, COOH) ppm; 13C NMR (125 MHz, DMSO-d6): ꢃ ¼ 22.27 (ꢁ-
CH3), 53.43, 55.43, 58.90, and 62.69 (C3, C4, Cꢀ, ArOCH3), 114.20 (C30, C50), 118.08 (C20, C60),
131.66 (C10), 155.47 (C40), 164.68 (CON), 170.21 (COOH) ppm.
(1R, 2R, 4R, 5S)-6-(4-Methoxyphenyl)-2-methyl-7-oxo-3-oxa-6-azabicyclo[3.2.0]
hept-4-yl 4-Bromobenzoate (22a, C20H18BrNO5)
4-Bromobenzoyl chloride (80.0 mg, 0.36mmol) was added to the solution of compound 19a (80.0mg,
0.32mmol) in pyridine (0.4cm3) in the presence of a catalytic amount of DMAP. The mixture was
stirred for 1 d, diluted with water (2cm3), the precipitate was dissolved in ether (5cm3), and the

Synthesis of Enantiomerically Pure 2-Isoxacephems
683
aqueous pyridine solution was extracted with ether (3 ꢄ 2 cm3). The ethereal phases were combined,
washed with brine, and dried (MgSO4).
The ethereal solution was concentrated to dryness (0.16 g oil), purified by preparative TLC
(CH2Cl2:EtOAc¼ 10:2.5, Rf(22a): 0.80) to give 22a (90.0 mg, 65%). Mp 152–153ꢂC (CH2Cl2);
32
½ꢀꢅd ¼ 286:3ꢂ gꢁ1 cm3 dmꢁ1; IR (KBr): ꢂꢀ¼ 1736 (CO), 1720 (CO), 1594, 1512 (Ar), 1400, 1360,
1272, 1244 and 1140 (COC), 1096, 944, 832cmꢁ1; 1H NMR (500 MHz): ꢃ ¼ 1.61 (d, JH2;CH ¼ 6.2 Hz,
3
CH3), 3.81 (s, ArOCH3), 3.84 (dd, JH5,H1 ¼ 4.4, JH2,H1 ¼ 5.3 Hz, H1), 4.54 (qui, J ¼ 6.0Hz, H2), 4.61
(d, JH1,H5 ¼ 4.0 Hz, H5), 6.92 (d, Jortho ¼ 8.9 Hz, H30, H50), 7.51 (d, Jortho ¼ 8.9 Hz, H30, H50), 7.63 (d,
Jortho ¼ 8.0 Hz, H300, H500), 7.92 (Jortho ¼ 8.0 Hz, H300, H500) ppm; 13C NMR (125MHz): ꢃ ¼ 15.81
(CH3), 55.43, 56.12, 60.94, and 74.21 (CH3OAr, C1, C5, C2), 97.11 (C4), 114.71 (C30, C50),
117.73 (C20, C60), 128.19 (C400), 129.01 (C100), 130.83 (C10), 131.27 (C300, C500), 131.99 (C200, C600),
155.48 (C40), 161.47 (CON), 164.96 (COO) ppm.
X-Ray Structure Determination of 22a
Formula: C20H17BrNO5, formula weight: 431.26, crystal system: monoclinic, space group: P21,
3
ꢂ
˚
˚
a ¼ 7.323(1), b ¼ 12.428(1), c ¼ 10.803(2) A, ꢁ ¼ 109.04(3) , V ¼ 929.4(2) A . 4235 reflections
(including a full set of Friedel opposites) were collected on an Enraf-Nonius CAD4 diffractometer
of which 3690 were unique and the intenisty of 3645 were greater than 2s (I). An empirical absorption
correction [15] was applied to the data (max. and min. transmission factors were 0.8757 and 0.7973).
The structure was solved by direct methods [16] and refined by anisotropic full matrix least-squares
[17] on F2. Final R2, wR2 values were 0.0623, 0.1513 for all and 0.0620, 0.1506 for I ¼ 2s (I). The
absolute structure parameter was ꢁ0.01(2) [18]. The structure plot was prepared using the PLATON
[19] program. Data have been deposited with the Cambridge Crystallographic Data Centre, deposition
number CCDC 220364.
Acknowledgements
Authors wish to thank the Hungarian Scientific Foundation (OTKA T 14200 and 37875) for financial
ꢁ
support. The authors are also indebted to Dr. Aron Sz€oll€ossy for his contribution by measuring NMR
ꢁ
spectra, Cs. Peltz for MS spectra, and K. Ofalvi for recording IR spectra. Our thanks go to H.
Medzihradszky-Schweiger for performing micro-analysis.
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Z. Santa et al.: Synthesis of Enantiomerically Pure 2-Isoxacephems
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