Strategies for the formation of 1-dethia-1-oxa-cephams

Article abstract of DOI:10.1016/S0040-4020(00)00405-1

The paper describes three possible routes for the formation of 1-dethia-1-oxa-cephams. The first two routes: (a) [2+2]cycloaddition to chiral vinyl ethers and (b) condensation of 4-acetoxyazetidin-2-one to chiral alcohols, are followed by the ring closure step involving N-alkylation. The third route (c) consists of N-alkylation prior to the cyclization step. In order to compare routes (a), (b) and (c), diastereomeric 1-dethia-3-(4-methoxybenzyloxy)-1-oxacephams were synthesized using three possible strategies. While the comparison of stereoselectivities of the [2+2]cycloaddition method (a) and the condensation (b) shows unequivocally the advantage of the former, the route (c) leads to the reverse direction of asymmetric induction relative to the first two steps and offers the highest asymmetric induction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00405-1

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 5553±5562
Strategies for the Formation of 1-Dethia-1-oxa-cephams
*
Ç
Z. Kaøuza, B. Furman, P. Krajewski and M. Chmielewski
Institute of Organic Chemistry of the Polish Academy of Sciences, 01-224 Warsaw, Poland
Received 11 August 1999; accepted 3 December 1999
AbstractÐThe paper describes three possible routes for the formation of 1-dethia-1-oxa-cephams. The ®rst two routes: (a) [212]cyclo-
addition to chiral vinyl ethers and (b) condensation of 4-acetoxyazetidin-2-one to chiral alcohols, are followed by the ring closure step
involving N-alkylation. The third route (c) consists of N-alkylation prior to the cyclization step. In order to compare routes (a), (b) and (c),
diastereomeric 1-dethia-3-(4-methoxybenzyloxy)-1-oxacephams were synthesized using three possible strategies. While the comparison of
stereoselectivities of the [212]cycloaddition method (a) and the condensation (b) shows unequivocally the advantage of the former, the route
(c) leads to the reverse direction of asymmetric induction relative to the ®rst two steps and offers the highest asymmetric induction. q 2000
Elsevier Science Ltd. All rights reserved.
Introduction
Recently, a new strategy for 1-dethia-1-oxacephams
synthesis, employing readily available 4-benzyloxy- and
4-vinyloxyazetidin-2-ones (2 and 3), has been reported in
our laboratory.7 The strategy consisted of N-alkylation of 2
or 3 with a specially prepared chiral fragment prior to the
cyclization step (Scheme 1, route c). The idea of this
strategy is based on the common observation that a ring
closure reaction usually affords better stereodifferentiation
than an intermolecular condensation. New building blocks 2
and 3 offer substantial advantage over 4-acetoxyazetidin-2-
one (1) owing to their stability under basic conditions,
which allow N-alkylation. The ring closure reaction
proceeds after transformation of the 4-benzyloxy or 4-vinyl-
oxy substituent into the 4-acyloxy group followed by a
nucleophilic displacement of the latter in the presence of a
Lewis acid catalyst.7 The vinyloxy substituent can also be
displaced by nucleophiles in certain cases.8
1-Dethia-1-oxacephems, 1-oxapenems, and clavams repre-
sent interesting groups of b-lactam antibiotics and inhibitors
of b-lactamase enzymes.1,2,3,4 All these compounds have
one structural feature in common which is an alkoxy
fragment present at C-4 of the azetidin-2-one ring. There-
fore the synthesis of these 1-oxabicyclic b-lactam anti-
biotics requires introduction of the 4-alkoxy fragment to
the azetidin-2-one ring at a certain stage of the synthetic
plan.
The most common strategy for the synthesis of 1-oxa-
bicyclic b-lactams involves nucleophilic substitution at
C-4 of the azetidin-2-one ring, which can constitute the
ring closure step, or which can be followed by formation
of the ®ve- or six-membered ring. The weak point of such a
strategy lies in a low asymmetric induction if C-3 of the
azetidin-2-one ring stays unsubstituted, or in exclusive
formation of the 3,4-trans-functionalized b-lactam ring if
C-3 bears a substituent.
So far, the strategy involving the azetidin-2-ones 2 and 3 has
been successfully performed for the 1-oxacepham synthesis
only.7,8 Three possible routes (a), (b) and (c) leading to the
1-oxabicyclic b-lactams 4 are presented in Scheme 1.
[212]Cycloaddition of chlorosulfonyl isocyanate (CSI) to
chiral vinyl ethers, having a chiral center next to the oxygen
atom (Scheme 1, route a),5 offers an alternative way for the
synthesis of 3-unsubstituted 4-alkoxyazetidin-2-ones to the
commonly used one which is based on the condensation of
commercially available 4-acetoxyazetidin-2-one (1) with
chiral alcohols (Scheme 1, route b).4 The latter methodology
provides low asymmetric induction,4 although an easy
nucleophilic substitution of the acyloxy group6 makes 1 a
very attractive intermediate for the synthesis of a variety of
clavams.4
Nucleophilic displacement at C-4 of the azetidin-2-one ring
proceeds via a ¯at intermediate which is supposed to have a
mesomeric cation structure 5. It should be noted, however,
that displacements performed on N-unsubstituted or N-silyl-
ated azetidin-2-ones proceed more readily.9
Keywords: azetidinones; oxacephams; stereocontrol.
* Corresponding author. E-mail: chmiel@ichf.edu.pl
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00405-1

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Z. Kal¤uzÇa et al. / Tetrahedron 56 (2000) 5553±5562
Scheme 1.
Facial differentiation in the reaction of the small, ¯at inter-
mediate 5 with chiral alcohols (route b) cannot be signi®-
cant. It has been shown,7b,8 however, that trapping an
O-protected chiral alcohol, having an sp3 electrophilic
center, by N-alkylation of 2 or 3 and subsequent ring closure
via nucleophilic substitution (route c), offers much better
stereoselectivity.
Results and Discussion
To demonstrate advantages offered by the [212]cyclo-
addition method (route a) over the condensation method
(route b), we selected four alcohols 6±9 which, when trans-
formed into vinyl ethers 10±13, afforded high asymmetric
induction with chlorosulfonyl isocyanate (Scheme 2).5b,d,10,11
In the present paper we intend to compare routes (a), (b) and
(c).
Alcohols 6±9 subjected to the condensation with 1
under standard conditions4 furnished the corresponding
Scheme 2.

Z. Kal¤uzÇa et al. / Tetrahedron 56 (2000) 5553±5562
5555
Scheme 3. i: CSI, Na2CO3 toluene, 2788; ii: Red-Al; iii: HF/Py; iv: TsCl; v: Bu4NBr, Na2CO3, CH3CN.
4-alkoxyazetidinones 14±17 with 9, 82, 20, and 44% d.e.,
respectively, whereas [212]cycloaddition of CSI to the
vinyl ethers 10±13 gave the same compounds 14±17 with
75, .97, .97 and 91% d.e., respectively (Scheme 2). Both
of the methods [212]cycloaddition (a) and condensation (b)
showed the same direction of asymmetric induction and
comparable yields which varied from 30 to 60%.
Directions of asymmetric induction in routes (a) and (b)
compared to route (c) are opposite, providing alternative
diastereomers. This is well illustrated in the formation of
tetracyclic b-lactams 18 and 19 (Scheme 3).5a,7b The
cycloaddition route (a) provides, after intramolecular
N-alkylation, the diastereomer 18 having the (R)-con®gu-
ration at the C-4 of the azetidinone ring,5a whereas the route
(c) gives, after intramolecular nucleophilic substitution, dia-
stereomer 19 having the (S)-con®guration at the same
carbon atom.7b Another example illustrates well the comple-
mentary direction of the asymmetric induction in routes (a)
and (c). [212]Cycloaddition of CSI to the vinyl ether 20
followed by intramolecular N-alkylation afforded the
cephams 21 and 22 in a ratio of 1:3, respectively.5d On the
other hand, a ring closure in 23 gave a corresponding
mixture of 21-ent and 22-ent in a ratio of 5:1 (Scheme
4).7b In other words, the [212]cycloaddition provides the
stereoisomer having anti H-2 and H-6 protons as the main
product, whereas the ring closure affords mainly the corre-
sponding stereoisomer having syn located H-2 and H-6
protons.
Owing to the rigid geometry of the transition state of the
[212]cycloaddition and de®ned conformation of vinyl
ethers, [212]cycloaddition offers excellent asymmetric
induction in certain cases.5,10,11 Recently we have proposed
a stereochemical model of the transition state for the
[212]cycloaddition of CSI to vinyl ethers, which allowed
us to predict the direction of asymmetric induction.12
The high asymmetric induction and the control of the
absolute con®guration of the bridge-head carbon atom of
the antibiotic are particularly important for the synthesis
of the b-lactamase inhibitors and natural clavams since
they do not have a substituent at the carbon atom next to
the b-lactam carbonyl group. The route (c) which, similarly
to the cycloaddition, proceeds via the well de®ned transition
state, usually provides high asymmetric inductions.7
In order to compare routes (a), (b) and (c), we synthesized
cephams 33 and 34. Alcohol 28, the starting material for the
Scheme 4.

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Z. Kal¤uzÇa et al. / Tetrahedron 56 (2000) 5553±5562
Scheme 5. i: PMBCl, NaH, DMF; ii: Bu4NHSO4, MeOH H2O, re¯ux; iii: TsCl, Py, CH2Cl2; iv: NaIO4, MeOH, H2O; v: NaBH4.
routes (a) and (b) was prepared from commercially available
1,3:4,6-di-O-benzylidene-d-mannitol (24) by a ®ve step
reaction sequence which is shown in Scheme 5. In both
routes (a) and (b), 28 was transformed into a mixture of
two diastereomeric products 29 and 30.
by its degradation in the presence of a TMS-tri¯ate±
triethylamine mixture.13 [212]Cycloaddition of CSI to 32
in the presence of sodium carbonate gave 29 in 52% yield
with 25.6% d.e. (Scheme 6).
In order to prove the con®gurations of 29 and 30, the
epimeric mixtures obtained via route (a) and (b) were
subjected to intramolecular N-alkylation to afford respective
mixtures of 33 and 34 which were separated into pure
components. The ratios of 33 and 34 re¯ected those of 29
and 30 in the substrate of the intramolecular alkylation. The
The alcohol 28 treated with 4-acetoxyazetidinone (1) under
standard reaction conditions4 afforded 4-alkoxyazetidinone
29 in a 68% yield with d.e. 13.0%. On the other hand, 28
was transformed into the vinyl ether 32 via a two step pro-
cedure involving formation of the mixed acetal 31 followed
Scheme 6. i: 1, Pd(OAc)2, PhMe, Et3N; ii: ethyl vinyl ether, TFA; iii: TMSOTf, Et3N, CH2Cl2; iv: CSI, Na2CO3, PhMe; v: Red-Al.

Z. Kal¤uzÇa et al. / Tetrahedron 56 (2000) 5553±5562
5557
Figure 1. NOEs (%) proving the relative con®gurations of 33 and 34.
absolute con®guration at C-6 of the cephams 33 and 34 was
proved by NOE measurements (Cf. Experimental). In the
case of 34, irradiation of the signal due to H-6 (d 4.96) was
found to enhance the intensity of the signal due to H-2b (d
3.71) by 11.5% and H-4b (d 3.02) by 2.9%. Conversely, the
signal due to H-6 was enhanced by 4.5% when H-2b was
irradiated. The irradiation of the signal due to H-2b
enhanced the signal of H-3 by 4.4% and H-4b by 9.3%.
In the case of 33, the picture is more complicated due to
overlapping of the H-2b and H-7b signals. Irradiation of the
signal due to H-6 (d 4.89) enhanced the intensity of H-4a (d
4.07) by 13.6% whereas it did not show any spin interaction
with H-4b (d 3.35). Spin interaction was found between the
H-4b and H-3 protons; irradiation of H-4b enhanced the
intensity of H-3 (d 3.57) by 6.2% (Fig. 1).
sulfonyl)-2,3-di-O-(p-methoxybenzyl)-d-glycerol 36 from
2,3-O-isopropylidene-d-glycerol (Scheme 7).14 Compound
36 was used for N-alkylation of azetidinone 3 followed by
the cyclization step (route c). This reaction sequence should
eventually provide enantiomeric forms of cephams 33 and
34. Formation of 33-ent and 34-ent does not affect,
however, the comparison of stereochemical pathways of
routes (a), (b) and (c).
N-alkylation of azetidinone 3 by compound 36 afforded 37
as a mixture of two diastereomers in 24% yield only. Due to
the low yield of formation of 37 from 36, we prepared the
tri¯ate 42 from the known 3815 by a seven step transfor-
mation (Scheme 8). The reaction sequence shown in
Scheme 8 is different from the known literature procedure.16
Due to the sensitivity of p-methoxybenzyl protection to
acidic conditions, allyl groups were removed using a three
For the route (c) we synthesized 1-O-(p-chlorophenyl-
Scheme 7. i: Ref. 14; ii: 4-methoxybenzyl 2,2,2-trichloroacetimidate, CSA, CH2Cl2; iii: 3, Bu4NHSO4, BuLi.
Scheme 8. i: PMBCl, NaH, DMF; ii: KOt-Bu, DMSO; iii: O3/Me2S; iv: MeONa, MeOH; v: NaIO4, H2O, MeOH; vi: NaBH4; vii: Tf2O, lutidine, CH2Cl2.

5558
Z. Kal¤uzÇa et al. / Tetrahedron 56 (2000) 5553±5562
Scheme 9.
step reaction sequence to give a good overall yield. N-alkyl-
ation of 3 by 42 afforded 37 in 78% yield. Ozonolysis of the
vinyl group in 37 yielded the 4-formyloxy derivative 43
which was subjected to ring closure in the presence of a
Lewis acid catalyst to give a mixture of 33-ent and 34-ent
in the proportion 3:7, respectively (Scheme 9). The direction
of asymmetric induction was found to be opposite to that
noticed for formation of a mixture of 33/34 using routes (a)
and (b).
shows unequivocally the advantage of the former, the
route (c) which leads to the reverse direction of asymmetric
induction than (a) and (b), looks to be the most attractive
one. The application of the route (c) is likely to be limited,
however, to the synthesis of 1-oxacephams. So far, the
formation of clavams using route (c) has been unsuccessful.
Experimental
The geometry of the transition state of the nucleophilic
substitution at C-4 of the azetidin-2-one ring in the route
(c) is probably like that of the product. Examination of
the coupling constants between the protons of the six-
membered ring in the cephams 33 and 34 (33-ent and 34-
ent) provide evidence that both, due to the introduction of a
four-membered ring, exist in distorted chair conformations;
consequently the transition state of the ring closure should
be chair-like (Fig. 2).
Optical rotations were measured with a JASCO Dip-360
digital polarimeter. IR spectra were obtained with a FT-
IR-1600 Perkin±Elmer spectrophotometer. 1H NMR spectra
were recorded with a Bruker AM 500 spectrometer. Mass
spectra were recorded with a AMD 604 mass spectrometer.
Column chromatography was performed on Merck Kiesel
gel (230±400 mesh). Ozonolysis was performed on BuÈchi
Ozone-Generator OZI.
Compounds 6±9 were obtained according to known pro-
cedures.5b,d,10,11
It has been shown by X-ray crystallography that the nitrogen
atoms in 1-oxacephams displays a ¯at sp2 hybridization17
contrary to that in 1-oxacephems which is shown to be
slightly pyramidal.18 Bearing in mind the chair-like tran-
sition state of the ring closure, the preference of the 34-
ent formation testi®es that the quasi-axial position of the
p-methoxybenzyloxy group at C-2 is preferred. The prefer-
ence of the axial position of many substituents at C-5 of
1,3-oxazines has been reported in the past.19
The 4-alkoxyazetidin-2-ones 14±17 were obtained from the
respective alcohols (6±9) according to the procedure
described below.
A solution of alcohol 6±9 (0.1 mmol) and palladium acetate
(0.005 g, 0.02 mmol) in toluene (5 mL) was treated under
argon with a solution of 4-acetoxy-2-azetidinone (1)
(0.026 g, 0.2 mmol) and triethylamine (28 mL, 0.2 mmol)
in dry toluene 1 mL. After 24 h of stirring, the brown resi-
due was ®ltered and washed with ethyl acetate. The organic
While the comparison of diastereoselectivities of the
[212]cycloaddition method (a) and the condensation (b)
Figure 2. Stereochemical models of transition states of the ring closure reactions.

Z. Kal¤uzÇa et al. / Tetrahedron 56 (2000) 5553±5562
5559
solution was washed with water, dried and evaporated. The
yellow oils were puri®ed by chromatography using hexane:
ethyl acetate 7:3 v/v as an eluent to afford corresponding
products 14±17. The spectroscopic and analytical data of
the b-lactams 14±17 were published before.5e,5d,10,11
cooling (ice-water), the ®ltrate was treated with NaBH4
(0.23 g, 6.0 mmol) and the mixture was stirred for 2 h.
Subsequently, the mixture was adjusted to pH 8 by the care-
ful addition of AcOH at 08C, and it was extracted 4 times
with ethyl acetate. The extract was dried over Na2SO4, and
evaporated. The residue was chromatographed on silica gel
to afford 28 (1.65 g, 75%) as an oil. [a]Dˆ220.4 (cˆ0.5,
1,3:4,6-Di-O-benzylidene-2,5-bis-O-(p-methoxybenzyl)-
d-mannitol (25). A suspension of sodium hydride (60% oil
dispersion, 1.60 g, 40.0 mmol) in dry DMF (70 mL) was
cooled to 08C and 1,3:4,6-di-O-benzylidene-d-mannitol
(5.38 g, 15.0 mmol) dissolved in DMF (20 mL) was added
slowly. The reaction was stirred for 30 min and p-methoxy-
benzyl chloride (3.64 mL, 36.0 mmol) was added. The
mixture was stirred for 1.5 h at room temperature, diluted
with ether, washed, dried (MgSO4), and evaporated. The
residue was puri®ed on a silica gel column using hexane:
ethyl acetate 8:2 v/v as an eluent to afford 25 (7.9 g, 85%).
[a]Dˆ230.4 (cˆ1.0, CH2Cl2); IR (CH2Cl2): 1260,
1
CH2Cl2); IR (CH2Cl2): 1176, 1365, 1514, 2955 cm21; H
NMR (CDCl3): d 7.79 and 7.34 (m, 4H, Ar-H); 7.21 and
6.86 (m, 4H, Ar-H); 4.52 (2d, 2H, benzyl, Jˆ11.3 Hz); 4.11
(d, 2H, H-3a,3b); 3.80 (s, 3H, OMe); 3.75±3.60 (m, 2H,
H-1a,1b); 3.58 (m, 1H, H-2); 2.45 (s, 3H, Me); 1.82 (t,
1H, OH). MS (HR, LSIMS) m/z (M1Na)1, calcd for
C18H22O6NaS: 389.10349. Found: 389.10372.
(2S)-1-O-(10-Ethoxyethyl)-2-O-(p-methoxybenzyl)-3-O-
(p-toluenesulfonyl)glycerol (31). A solution of alcohol 28
(1.10 g, 3.0 mmol) in ethyl vinyl ether (10 mL) was cooled
to 08C and treated with tri¯uoroacetic acid (2 mL). The
mixture was left at room temperature until disappearance
of the substrate (48 h). Subsequently, with stirring, pul-
verized sodium carbonate (0.10 g) was added. After 1 h
the solution was ®ltered and the ether was evaporated.
The crude product was puri®ed on a silica gel column
using hexane:t-butyl methyl ether 9:1 v/v as an eluent to
afford 31 as a 1:1 diastereomeric mixture (1.27 g, 97%).
1554 cm21 1H NMR (CDCl3): d 7.45±6.70 (m, 16H,
;
Ar-H); 5.36 (s, 2H, acetal); 4.52 (2d, 4H, benzyl,
Jˆ11.6 Hz); 4.25 (dd, H-1a, H-6a); 3.67 (s, 6H, OMe);
Anal. calcd for C36H38O8: C, 72.22; H, 6.40. Found: C,
72.21; H, 6.53.
2,5-Di-O-(p-methoxybenzyl)-d-mannitol (26). A solution
of 25 (5.94 g, 10.0 mmol) in methanol/water (10:1) (20 mL)
was stirred in the presence of Bu4NHSO4 (0.80 g, 2.0 mmol)
at 608C. Stirring and heating were continued until dis-
appearance of the substrate (8 h). After neutralization with
sodium hydrogen carbonate, evaporation of the solvent, the
crude product was puri®ed by chromatography to afford 26
(1.63 g, 40%). [a]Dˆ29.0 (cˆ1.9, methanol); IR (CH2Cl2):
IR (CHCl3): 1177, 1362, 1456, 1612 cm21 1H NMR
;
(CDCl3): d signals due to acetal protons of two dia-
stereomers 4.66, 4.61 (2q, 1H, O±CH(CH3)±O,
Jˆ5.3 Hz); MS (HR, LSIMS) m/z (M1Na)1, calcd for
C22H30O7NaS: 461.16098. Found: 461.16412.
1
1264, 1533 cm21; H NMR (CDCl3): d 7.23 and 6.86 (m,
(2S)-2-O-(p-Methoxybenzyl)-3-O-(p-toluenesulfonyl)-1-
O-vinylglycerol (32). A solution of 31 (0.88 g, 2.0 mmol) in
dichloromethane (2 mL) was treated with triethylamine
(0.42 mL, 3.0 mmol) under nitrogen. Upon cooling to 08C,
the mixture was stirred and treated dropwise with TMS-
tri¯ate (0.50 mL, 2.6 mmol). Stirring and cooling were
continued until disappearance of the substrate (3 h). Sub-
sequently, the mixture was treated with 10% sodium
hydroxide (1 mL) and hexane (20 mL). Organic layer was
separated, dried and evaporated. The crude product was
puri®ed on a silica gel column using hexane:t-butyl methyl
ether 9.5:0.5 v/v as an eluent to give 32 (0.58 g, 75%).
[a]Dˆ217.0 (cˆ1.0, CH2Cl2); IR (CH2Cl2): 1362, 1615,
8H, Ar-H); 4.55 (2d, 4H, benzyl, Jˆ11.1 Hz); 3.89 (t, 2H,
H-3, H-4, Jˆ6.1 Hz); 3.79 (s, 6H, OMe); 3.82±3.75 (m, 4H,
H-1a,1b, H-6a,6b); 3.61±3.52 (m, 2H, H-2, H-5); 2.84 (d,
2H, OH); 2.31 (t, 2H, OH). Anal. calcd for C22H30O8: C,
62.55; H, 7.16. Found: C, 62.32; H, 6.90.
2,5-Di-O-(p-methoxybenzyl)-1,6-di-O-(p-toluenesulfonyl)-
d-mannitol (27). Compound 26 (1.59 g, 4.0 mmol) in dry
pyridine (40 mL) was cooled to 08C and treated with
p-toluenesulfonyl chloride (1.64 g, 8.6 mmol). The
temperature of reaction was allowed to rise to room
temperature and mixture was left until disappearance of
the substrate (TLC, 24 h). Subsequently, the solution was
poured into ice-water (100 mL) and extracted with t-butyl
methyl ether (3£50 mL). Combine extracts were dried and
evaporated. The crude product was puri®ed by chroma-
tography to afford 27 (2.60 g, 90%). [a]Dˆ224.9 (cˆ1.2,
1
1637 cm21; H NMR (CDCl3): d 7.78 and 7.31 (m, 4H,
Ar-H); 7.21 and 6.85 (m, 4H, Ar-H); 6.37 (dd, 1H, H-10,
Jˆ6.8, 14.3 Hz), 4.52 (s, 2H, benzyl); 4.16 (dd, 1H, H-3a,
Jˆ4.7, 10.4 Hz); 4.12 (dd, 1H, H-20trans, Jˆ2.3, 14.5 Hz);
4.07 (dd, 1H, H-3b, Jˆ5.3, 10.4 Hz); 4.01 (dd, 1H, H-20cis,
Jˆ2.3, 6.8 Hz); 3.83 (m, 1H, H-2); 3.80 (s, 3H, OMe); 3.69
(d, 2H, H-1a,1b); 2.44 (s, 3H, Me). MS (HR, LSIMS) m/z
(M1Na)1, calcd for C20H24O6NaS: 415.11914. Found:
415.12294.
1
CH2Cl2); IR (CH2Cl2): 1176, 1250, 1514 cm21; H NMR
(CDCl3): d 7.77, 7.31 and 7.16, 6.85 (4£m, 16 H, Ar-H);
4.45 (2d, 4H, benzyl, Jˆ11.3 Hz); 4.25 (dd, H-1a, H-6a,
Jˆ2.7 Hz); 3.79 (s, 6H, OMe); 3.77 (m, 4H, H-1a,1b,
H-6a,6b); 3.58 (m, 2H, H-2, H-5); 2.84 (d, 2H, OH); 2.31
(t, 2H, OH). MS (HR, LSIMS) m/z (M1Na)1, calcd for
C22H30O7NaS: 753.20154. Found: 753.19712.
(2R, 40S)- and (2R, 40R)-2-O-(Azetidin-20-onyl-40)-2-O-
(p-methoxybenzyl)-3-O-(p-toluenesulfonyl)glycerol. (29
and 30). Method A: To a solution of CSI (61 mL,
0.7 mmol) in toluene (1 mL) anhydrous Na2CO3 (0.08 g)
was added. The mixture was cooled to 2788C and upon
stirring was treated dropwise with vinyl ether 32 (0.20 g,
0.5 mmol) in toluene (1 mL). Stirring and cooling were
maintained for 1.5 h. Subsequently the mixture was diluted
(2S)-2-O-(p-Methoxybenzyl)-3-O-(p-toluenesulfonyl)-
glycerol (28). A solution of NaIO4 (0.86 g, 4.0 mmol) in
water (30 mL) was added to an ice-cooled solution of 27
(2.20 g, 3.0 mmol) in methanol/water 1:1 (20 mL). After
being stirred for 10 min, the mixture was ®ltered. While

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Z. Kal¤uzÇa et al. / Tetrahedron 56 (2000) 5553±5562
with toluene (5 mL) and treated at 2788C with 1 M Red-Al
in toluene. After 30 min temperature was allowed to rise to
room temperature and water (0.4 mL) was added. The
mixture was stirred for additional 30 min. Subsequently it
was ®ltered through Celite and evaporated. Puri®cation on a
silica gel column using hexane:ethyl acetate 7:3 v/v as an
eluent gave a mixture of 29 and 30 (0.12 g, 52%, d.e.
were used for reference and irradiated spectra. The
estimated precision of the experimental NOE values is 1%
of NOE.
(R)-1-O-p-Chlorobenzenesulfonyl-2,3-di-O-p-methoxy-
benzyl glycerol (36). To a solution of compound 3514
(10 mmol, 2.66 g) in dry methylene chloride (50 mL) was
added p-methoxybenzyl-2,2,2-trichloroacetimidate (40 mmol,
11.3 g) and 10-camphorosulfonic acid (1 mmol, 0.232 g).
After stirring for 24 h at r.t., the precipitate was ®ltered
off, washed with hexane±methylene chloride 1:1 mixture,
®ltrates were combined, and concentrated. Crude product
was puri®ed on silica gel using hexane:t-butylmethyl ether
4:1, v/v as an eluent to afford 36 as a white crystals 2.96 g
(58 %), mp. 85.5±86.58C; [a]Dˆ1.4 (cˆ1.0, CH2Cl2); IR
(CH2Cl2): 1623, 1514 cm21; 1H NMR (CDCl3): d 4.48 and
4.39 (2£bs, 4H, benzyl); 4.22 (dd, 1H, H-1a, Jˆ10.4,
4.0 Hz); 4.11 (dd, 1H, H-1b, Jˆ10.4, 5.7 Hz); 3.81 (s, 6H,
OMe); 3.80±3.69 (m, 1H, H-2); 3.47 (d, 1H, H-3a,
Jˆ0.8 Hz); 3.44 (d, 1H, H-3b, Jˆ1.8 Hz);. MS (LSIMS,
HR) m/z: (M1Na)1 calcd for C25H27O7ClNaS: 529.10637.
Found: 529.10779. Anal. calcd for C25H27O7ClS: C, 59.23;
H, 5.37; Cl, 6.99; S, 6.32. Found: C, 59.15; H, 5.43; Cl, 7.04;
S, 6.37.
1
25.6%). IR (CHCl3): 1768, 3425 cm21; H NMR (CDCl3)
signals due to 29 inter alia: 4.95 (dd, 1H, H-40, Jˆ1.5,
4.0 Hz); 3.04 (ddd, 1H, H-30b, Jˆ2.6, 5.2, 15.1 Hz); 2.73
(ddd, 1H, H-30a, Jˆ0.6, 1.5, 15.1 Hz), signals due to 30 inter
alia: 5.01 (dd, 1H, H-40, Jˆ1.5, 3.9 Hz); 3.02 (ddd, 1H,
H-30b, Jˆ2.7, 5.2, 15.1 Hz); 2.79 (ddd, 1H, H-30a, Jˆ0.6,
1.5, 15.1 Hz). MS (HR, LSIMS) m/z (M1H)1, calcd for
C21H26O7NS: 436.14300. Found: 436.14166.
Method B: The title compounds 29 and 30 (68%, d.e.
13.0%) were prepared from 4-acetoxy-2-azetidinone (1)
and 28 according to the procedure described for compounds
14±17.
(3S, 6S)- and (3S, 6R)-3-(p-Methoxybenzyloxy)-1-
oxacephams (33 and 34). A mixture of 33 and 34 was
obtained from a mixture of 29 and 30 according to the
procedure described earlier (87%).5a Compounds 33 and
34 were separated on a silica gel column using CH2Cl2:
toluene:t-butyl methyl ether 6:2:2 v/v as an eluent.
3,4-Di-O-allilo-1,2,5,6-tetra-O-p-methoxybenzyl-d-mannitol
(39). Sodium hydride (130 mmol, 5.2 g 60% in oil) was
washed with hexane and suspended in dry DMF (150 mL)
under argon atmosphere. Into this mixture mannitol 3815
(25 mmol, 6.54 g) in DMF (50 mL) was added dropwise
with stirring at rt. After 20 min PMB chloride (110 mmol,
,15 mL) was added dropwise during 30 min. Stirring was
continued for 2 h. Subsequently the mixture was poured into
cold water and extracted with toluene (3£200 mL). The
extract was washed with water, dried (MgSO4), and evapo-
rated. The crude product was puri®ed on silica gel using
hexane:ethyl acetate 4:1, v/v as an eluent to afford 39 as
an oil, (15.5 g, 84%).[a]Dˆ12.7 (cˆ0.5, CH2Cl2); IR
Major product 33, less polar (TLC): [a]Dˆ254.0 (cˆ0.2,
1
CH2Cl2); IR (CH2Cl2): 1758 cm21; H NMR (CDCl3): d
4.89 (d, 1H, H-6, Jˆ3.2 Hz); 4.49 (2d, 2H, benzyl,
Jˆ11.4 Hz); 4.14 (ddd, 1H, H-2a, Jˆ1.7, 5.9, 12.9 Hz);
4.07 (ddd, 1H, H-4a, Jˆ1.7, 4.5, 11.4 Hz); 3.57 (m, 1H,
H-3); 3.35 (dd, 1H, H-4b, Jˆ11.4 Hz); 3.10 (ddd, 1H,
H-7a, Jˆ1.8, 3.3, 14.9 Hz); 2.77 (ddd, 1H, H-2b, Jˆ1.7,
9.6, 12.9 Hz); 2.76 (dd, 1H, H-7b, Jˆ0.5, 14.9 Hz); MS
(HR, LSIMS) m/z (M1H)1, calcd for C14H18O4N:
264.12360. Found: 264.12184.
1
(CH2Cl2): 2864, 1613, 1514 cm21; H NMR (CDCl3): d
Minor product 34, more polar (TLC): [a]Dˆ70.3 (cˆ0.2,
7.23±6.83 (m, 16H,): 5.84 (ddt, 2H, ±CHv, Jˆ17.2,
10.4, 5.7 Hz); 5.15 (ddd, 2H, vCHaHb, Jˆ17.2, 3.4,
1.6 Hz); 5.05 (ddd, 2H, vCHaHb, Jˆ10.4, 3.4, 1.2 Hz);
4.50 (dd, 4H, benzyl, Jˆ11.3 Hz); 4.43 (2d, 4H, PMB,
Jˆ11.3 Hz); 4.10 (ddt, 2H, CHaHbCHv, Jˆ12.5, 5.7,
1.6 Hz); 4.02 (ddt, 2H, CHaHbCHv, Jˆ12.5, 5.7, 1.2 Hz);
3.78 (bs, 12H, OMe); 3.82±3.76 (m, 6H, H-1a, H-2, H-3,
H-4, H-5, H-6a); 3.62 (dd, 2H, H-1b, H-6b, Jˆ11.4, 5.0 Hz).
MS (LSIMS, HR) m/z: (M1Na)1 calcd for C44H56O10Na:
765.36147. Found: 765.36495. Anal. calcd for C44H56O10:
C, 71.14; H, 7.33. Found: C, 70.28; H, 7.14.
1
CH2Cl2); IR (CH2Cl2): 1766 cm21; H NMR (CDCl3): d
4.96 (d, 1H, H-6, Jˆ3.2 Hz); 4.55 (2d, 2H, benzyl,
Jˆ11.3 Hz); 4.17 (dt, 1H, H-2a, Jˆ2.4, 12.7 Hz); 4.04
(ddd, 1H, H-4a, Jˆ1.4, 2.4, 14.4 Hz); 3.71 (dd, 1H, H-2b,
Jˆ1.2, 12.7 Hz); 3.34 (m, 1H, H-3); 3.17 (ddd, 1H, H-7a,
Jˆ1.2, 3.3, 14.9 Hz); 3.02 (ddd, 1H, H-4b, Jˆ1.6, 2.8,
14.4 Hz); 2.96 (dd, 1H, H-7b, Jˆ0.5, 14.9 Hz); MS (HR,
LSIMS) m/z (M1H)1, calcd for C14H18O4N: 264.12360.
Found: 264.12162.
Steady-state NOE experiments
1,2,5,6-Tetra-O-p-methoxybenzyl-d-mannitol (40).
A
solution of 39 (11.02 g, 14.8 mmol) in DMSO (100 mL)
was treated with potassium t-butoxide (8.32 g, 74.3 mmol)
under nitrogen. The mixture was stirred at 608C until dis-
appearance of the substrate (2 h). Subsequently it was
poured into ice-water (500 mL) and extracted with t-butyl
methyl ether (3£100 mL). Combine extracts were dried and
evaporated. The crude product was dissolved in CH2Cl2
(150 mL) and 3 mL of ethanolic saturated solution of
ozonizable dye (Sudan red 7B)20 was placed in the three-
necked ¯ask, equipped with thermometer, bubbling tube
and ozone outlet. The solution was stirred and upon cooling
Steady-state NOEs for 33 (ca. 10 mg in 0.7 ml C6D6) and 34
(ca. 10 mg in 0.7 ml C6D6) were measured at room tempera-
ture on a Varian INOVA 500 spectrometer using a routine
program for multiplet irradiation (Fig. 1). The samples were
degassed to minimize external relaxation. The longest 1H T1
determined for the samples were used for setting up the total
irradiation time necessary to produce steady-state NOEs.
The experimental conditions used were: 15 s total irradia-
tion, 4 s acquisition, 5000 Hz spectral width. NOE inten-
sities were calibrated by using a reference signal that was
unaffected by the irradiation, and the same phase parameters

Z. Kal¤uzÇa et al. / Tetrahedron 56 (2000) 5553±5562
5561
to 2788C, ozone was bubbled through. After about 20 min,
the deep red color of the reaction mixture turned to light
yellowish. The ozone generator was switched off, and
oxygen was passed through the solution for 2 min. Dimethyl
sul®de (9.5 ml) was added in one portion, and stirring was
continued at 2788C for 20 min. The reaction mixture was
brought to r.t. and the solvent was evaporated. The crude
mixture was dissolved in methanol and treated with triethyl-
amine (5 mL) and mixture was left for (24 h), until dis-
appearance of the substrate (TLC). After 24 h the solution
was evaporated to dryness. The yellow oil was chromato-
graphed using hexane:ethyl acetate 1:1, v/v as an eluent to
give a 40 (7.8 g). Oil, [a]Dˆ212.4 (cˆ0.7, CH2Cl2); IR
mixture, upon cooling to 2788C, butyllithium (21 mmol,
8.4 ml of 2.5 M/hexane) was added and after 20 min
sulfonate 36 (1.673 g, 3.3 mmol) in a THF solution
(10 ml) was added. Stirring was continued at 2788C for
15 min and subsequently the mixture was allowed to
warm to rt. Stirring was maintained for additional 24 h
and then the reaction mixture was poured into water
(300 ml) and extracted with t-butyl-methyl ether
(3£150 ml). Combined extracts were washed with water,
dried (MgSO4) and evaporated. Crude product was puri®ed
on silica gel using hexane:t-butylmethyl ether 2:3, v/v as an
eluent to afford 37 as an oil, 0.325 g (23%). IR (CH2Cl2):
1766, 1641, 1613 cm21; 1H NMR (CDCl3) selected data for
the 1:1 mixture of diastereomers: d 6.33 and 6.32 (2£dd,
2H, OCHv, Jˆ14.3, 6.8); 5.23 and 5.13 (2 dd, 2H, H-4,
Jˆ3.6, 1.1 Hz); 3.02 and 2.98 (2 dd, 2H, H-3a, Jˆ14.8,
3.6 Hz); 2.79, 2.78 (2 bd, 2H, H-3b, Jˆ14.8 Hz); MS
(LSIMS, HR) m/z: (M1Na)1 calcd for C24H29O6NNa:
450.189258. Found: 450.190706. Anal. calcd for
C24H29O6N: C, 67.43; H, 6.84; N, 3.28. Found: C,67.40;
H, 6.88; N, 2.99.
;
(CH2Cl2): 3473, 2934, 1613, 1514 cm21 1H NMR
(CDCl3): d 7.25±6.81 (m, 16H, Ar-H); 4.63 and 4.50
(2£d, 4H, PMB, Jˆ11.2 Hz); 4.47 (s, 4H, PMB); 3.90 (t,
2H, H-3, H-4, Jˆ5.8 Hz); 3.79, 3.78 (2£s, 12H, OMe);
3.79±3.69 (m, 2H, H-2, H-5); 3.69 (dd, 2H, H-1a, H-6a,
Jˆ10.0, 4.3 Hz); 3.61 (dd, 2H, H-1b, H-6b, Jˆ10.0,
4.8 Hz); 3.03 (d, 2H, OH, Jˆ5.8 Hz). MS (LSIMS, HR)
m/z: (M1Na)1 calcd for C38H46O10Na: 685.29887. Found:
685.30309. Anal. calcd for C38H46O10: C, 68.84; H, 7.00.
Found: C, 68.59; H, 7.03.
Alkylation of 3 with crude tri¯ate 42. Alkylation of 3
(1.356 g, 12 mmol) with crude tri¯ate 42 (,9 mmol) was
performed as describe above. Reaction was completed after
1 h to afford 37 (3.02 g, 78%).
(2S)-2,3-Di-p-methoxybenzyl glycerol (41). A solution of
NaIO4 (7.6 g, 13.0 mmol) in water (100 mL) was added to
an ice-cooled solution of 40 (7.6 g, 11.5 mmol) in methanol/
water 1:1 (200 mL). After being stirred for 30 min, the
mixture was ®ltered. The ®ltrate, was treated with NaBH4
(0.378 g, 10.0 mmol) under ice-cooling, and the mixture
was stirred at 08C for 2 h. The mixture was adjusted to pH
8 by the careful addition of AcOH at 08C and extracted 4
times with ethyl acetate. The extracts were dried over
Na2SO4, and the solvent was evaporated. The residue was
chromatographed on silica gel using hexane:ethyl acetate
3:2, v/v as an eluent to afford 41 (5.5 g, 72%) as an oil.
[a]Dˆ221.08 (cˆ1.2, CHCl3), Lit. [a]Dˆ221.38 (cˆ1.0,
CHCl3).21
(4S,20S)- and (4R,20S)-1-[20,30-Di-(p-methoxybenzyl-
oxy)propan-10-yl]-4-formyloxyazetidin-2-one (43). The
solution of 37 (2.99 g, 7 mmol) in CH2Cl2 (100 mL) and
3 mL of ethanolic saturated solution of ozonizable dye
(Sudan red 7B)20 was placed in the three-necked ¯ask,
equipped with thermometer, bubbling tube and ozone outlet.
The solution was stirred and upon cooling to 2788, ozone
was bubbling. After about 15 min, the deep red color of the
reaction mixture turned to light yellowish. The ozone
generator was switched off, and oxygen was passed through
the solution for 2 min. Dimethyl sul®de (2 ml) was added in
one portion, and stirring was continued at 2788C for
20 min. The reaction mixture was brought to rt and the
solvent was evaporated. Crude product was puri®ed on
silica gel using hexane:t-butylmethyl ether 1:4, v/v) to
afford 43 as an oil, (2.01 g, 67%). IR (CH2Cl2): 1774,
(R)-2,3-Di-p-methoxybenzyl-1-O-tri¯uoromethanesulfonyl
glycerol (42). 2,6-Lutidine (12 mmol, ,1.4 ml) was
dissolved under argon in dry CH2Cl2 (20 ml) and after
cooling was added dropwise to 2208C tri¯ic anhydride
(10 mmol, ,1.7 ml). The mixture was stirred for 5 min
and then a solution of hydroxy compound 41 (3.0 g,
9 mmol) in CH2Cl2 (15 ml) was added dropwise. Stirring
and temperature were maintained for ,30 min (TLC
control). Subsequently the solution was warmed up to 08
and poured into ice-water (100 ml). The organic phase
was separated, washed with cold water (3£50 ml), dried
(MgSO4) and evaporated. The crude oil was dissolved in
t-butyl-methyl ether (,10 ml) and titrated with hexane
(,30 ml). The precipitate was ®ltered off through Celite
and the ®ltrate was concentrated to give crude tri¯ate 42,
which was promptly used for the next step without any
further puri®cation.
1
1731, 1612 cm21; H NMR (CDCl3) selected data for the
1:1 mixture of diastereomers: d 7.94 and 7.92 (2 d, 2H,
CHO, Jˆ0.5 Hz); 6.03 and 5.86 (2 bd, 2H, H-4,
Jˆ3.6 Hz); 3.15 and 3.14 (2 dd, 2H, H-3a, Jˆ15.0,
3.6 Hz), 2.86 and 2.84 (2 bd, 2H, H-3b Jˆ15.0 Hz), MS
(LSIMS, HR) m/z: (M1Na)1 calcd for C23H27O7NNa:
452.16852. Found: 452.16789. Anal. calcd for C23H27O7N:
C, 64.32; H, 6.34; N, 3.26. Found: C, 64.33; H, 6.60; N,
3.07.
(3S,6R)- and (3S,6S)-1-Dethia-3-(4-methoxybenzyloxy)-
1-oxacephams 33-ent and 34-ent. To a stirred suspension
of molecular sieves A-4 (,0.3 g) in CH2Cl2 (40 mL)
4-formyloxy-b-lactam 43 (2.5 mmol, 1.074 g) in 5 mL of
CH2Cl2 was added. After 5 min BF3´Et2O (1.0 mmol,
126 mL) was added in one portion. The mixture was stirred
for ,40 min (TLC control). The saturated solution of
NaHCO3 (10 mL) was added and stirring was continued
for 10 min. The organic phase was separated, washed with
(4S,20S)- and (4R,20S)-1-[20,30-Di-(p-methoxybenzyl-
oxy)propan-10-yl]-4-vinyloxyazetidin-2-one (37). Alkyl-
ation of 3 with 4-chlorobenzenesulfonate (36). To a
stirred suspension of ®ne powdered tetrabutylammonium
hydrogen sulfate (3.57 g, 10.5 mmol) in dry THF (70 ml)
under argon was added 3 (10 mmol, 1.13 g). Into this
1
water, dried (MgSO4) and evaporated. H NMR spectra of

5562
Z. Kal¤uzÇa et al. / Tetrahedron 56 (2000) 5553±5562
5. (a) KaøuzÇa, Z.; Furman, B.; Patel, M.; Chmielewski, M.
Tetrahedron: Asymmetry 1994, 5, 2179. (b) KaøuzÇa, Z.; Furman,
B.; Chmielewski, M. Tetrahedron: Asymmetry 1995, 7, 1719. (c)
Chmielewski, M.; KaøuzÇa, Z.; Abramski, W.; BeøzÇecki, C.;
crude product showed that reaction mixture was consisted of
oxacephams (33-ent) and (34-ent), in the proportion of 3:7
(NMR). Puri®cation on silica gel (eluent: hexane:ethyl
acetate 3:1!2:3, v/v) gave two fractions: ®rst fraction
contained 33-ent, oil 0.11 g (17%) [a]Dˆ53.3 (cˆ0.5,
CH2Cl2), second fraction (210 mg, 31%) consisted of
oxacepham 34-ent, [a]Dˆ270.9 (cˆ0.4, CH2Cl2).
Â
Grodner, J.; Mostowicz, D.; Urbanski, R. Synlett 1994, 539. (d)
KaøuzÇa, Z.; Furman, B.; Chmielewski, M. J. Org. Chem. 1997, 62,
3135.
6. Clauss, K.; Grimm, D.; Prossel, G. Liebigs Ann. Chem. 1974,
539.
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