A new synthetic approach to 5-dethia-4-methyl-5-oxacephems

Article abstract of DOI:10.1016/S0040-4020(03)00939-6

Starting from (L)-ethyl lactate and 4-vinyloxy-azetidin-2-one the diastereomeric (4S,6R)- and (4S,6S)-4-methyl-5-oxa-3-methylene and 3-oxo-cephams were obtained. The formation of the cepham skeleton proceeds with a diastereomeric excess up to 80%, depending on catalyst and reaction conditions. For comparison, the corresponding racemic cephams lacking a methyl at C-4 or with a gem-dimethyl group at C-4 were synthesized.

Full text of DOI:10.1016/S0040-4020(03)00939-6

Tetrahedron 59 (2003) 5893–5903
A new synthetic approach to 5-dethia-4-methyl-5-oxacephems
a
a
b
c
,
*
´
˙
Zbigniew Kałuza, Arkadiusz Kazimierski, Krzysztof Lewandowski, Kinga Suwinska,
Beata Szcze¸snaa and Marek Chmielewskia
aInstitute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
bInstitute of Chemistry, Podlasie University, 08-110 Siedlce, Poland
cInstitute of Physical Chemistry of the Polish Academy of Sciences, 01-224 Warsaw, Poland
Received 19 March 2003; revised 16 May 2003; accepted 12 June 2003
Abstract—Starting from (L)-ethyl lactate and 4-vinyloxy-azetidin-2-one the diastereomeric (4S,6R)- and (4S,6S)-4-methyl-5-oxa-3-
methylene and 3-oxo-cephams were obtained. The formation of the cepham skeleton proceeds with a diastereomeric excess up to 80%,
depending on catalyst and reaction conditions. For comparison, the corresponding racemic cephams lacking a methyl at C-4 or with a gem-
dimethyl group at C-4 were synthesized.
q 2003 Elsevier Ltd. All rights reserved.
The synthesis of 5-oxacephalotin1 and 5-oxacephamandol,2
characterized by a higher activity than their natural
congeners containing sulfur, as well as the isolation of
clavulanic acid,3 a potent inhibitor of b-lactamase enzymes,
directed attention of academic and industrial laboratories to
the synthesis of oxygen analogs of penicillins and
cephalosporins.4 – 6 There are four different synthetic
methods proposed for construction of the basic skeleton of
these compounds. Two of these involve nucleophilic
substitution at C-4 of the azetidin-2-one, carried out as an
inter- or intramolecular process4,6 and the remaining two
methods involve cycloaddition reactions between ketenes
and iminoethers,7 or between vinyl ethers and isocyanates.5
Thefirstoneisbasedonthe[2þ2]cycloadditionofisocyanates
to the chiral vinyl ethers resulting in a formation of 4-alkoxy-
azetidin-2-ones, suitable for further transformations.5 For
example, the oxacephem 2 [structurally related to OCP-9-176
(1)] was obtained in a few step synthesis from L-rhamnal.10
The alternative methodology, shown in Scheme 1,
employed 4-vinyloxyazetidin-2-one 3 which can be easily
N-alkylated with a chiral p-methoxybenzyl ether 4 contain-
ing a suitable leaving group.9 Subsequently, the vinyloxy
During 1988, the Merck and Meiji groups8 reported a new
oxacepham OCP-9-176 (1) with a 4b-methyl substituent.
Introduction of the 4b-methyl substituent to the oxacephem
skeleton apparently increases the stability of the antibiotics
to b-lactamases without significant change of the activity.
In the course of our studies on the syntheses of clavams and
5-oxacephams we have proposed two new methodologies.5,9
Keywords: 5-oxacephams; iminium cation stereoselective cyclization.
*
Corresponding author. Tel.: þ48-22-632-3221x2142; fax: þ48-22-632-
6681; e-mail: zkicho@icho.edu.pl
Scheme 1.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00939-6

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Z. Kałuz˙a et al. / Tetrahedron 59 (2003) 5893–5903
substituent can be oxidized to a 4-acyloxy residue. The
Lewis acid-promoted cyclization of 5 via nucleophilic
displacement of the 4-vinyloxy or 4-acyloxy group by the
oxygen atom of the p-methoxybenzyl ether led to the
mixture of oxacephams 7 and 8 (5:1 ratio, respectively).9
The favored geometry of the transition state of the
cyclization is probably closer to structure 6a, which does
not show an interaction between an axial methyl and the
iminium cation, than to structure 6b. The diastereo-
selectivity of the intramolecular substitution at C-4 of the
b-lactam ring in 5b is much better than that observed for the
intermolecular condensation of 4-acetoxy-azetidin-2-one
with chiral alcohols.11 In the present work we report studies
toward a stereo-controlled approach to the 4-methyl-5-
oxacephems bearing functional groups at the C-2, C-3
carbon atoms, amenable to further transformations.
compound 11 was obtained via benzylation with the p-
methoxybenzyl imidate in the presence of an acid catalyst,
according to Shimano et al.13 procedure. The Claisen
condensation of t-butyl acetate and lactate 11 according to
Pastor et al.14 led to b-ketoester 12 in 92% yield. The
bromination of 12 using copper (II) bromide in the presence
of a Koser’s reagent15 gave a mixture of starting ketoester
12, mono-bromide 13, and dibromide 14 in a 1:9:1 ratio,
respectively. Purification of the products by flash chroma-
tography on silica gel afforded unexpectedly compounds 13
and 14 in 37 and 34% yield respectively.
The 1H NMR spectra of equimolar amounts of 12 and 14 in
CDCl3 solution, recorded after 24 h, indicated the presence
of a mixture of 12, 13 and 14 in the same proportion as in the
crude bromination product. This experiment indicated that
the state of equilibrium exists between mono-bromide 13,
b-ketoester 12 and dibromide 14. The chromatographic
separation of the less-polar dibromide 14 shifts the
equilibrium of the reaction product back to the original
mixture. Therefore, the crude bromide 13 was used in the
next step. The alkylation of 3 with crude 13 proceeded
smoothly under phase-transfer conditions (K2CO3, Bu4NBr,
acetonitrile, RT) to give 15 in 52% yield as a mixture of two
diastereomers. The mixture 15 was not separated and
configurations of components were not assigned.
Retrosynthetic analysis depicted in Scheme 2 shows that
starting with ethyl L-lactate 9 and using methodology
involving the intermediary azetidinone 3 should provide an
attractive approach to the oxacepham 10. We assume that
the crucial step of the planned synthesis should proceed via
a low-energy transition state, like structure 6a. Conse-
quently, the (6R) configuration of compound 10 should be
expected.
Bearing in mind the above presented speculation, we
synthesized compound 13 from ethyl lactate 9 in a three-
step sequence. (Scheme 3). The p-methoxybenzylation of 9,
following the known procedure12 (NaH, PMB-Cl, DMF,
THF, RT), unexpectedly gave the racemic ether ^11, in
contrast with the published results. The optically pure
Based on our earlier results,10,11 we assumed that the
cyclization of 15 could proceed with a relatively high
stereoselectivity to give a mixture of oxacephams 16. Since
the nucleophilic substitution proceeds via iminium cation,16
the configuration at C-4 of the azetidin-2-one ring in the
Scheme 2.
Scheme 3. Reagents and conditions: (i) p-methoxybenzyl 2,2,2-trichloroacetimidate, 10-camphor-sulphonic acid, CH2Cl2, overnight at rt; (ii) HMDS-Li, THF,
2508C, 15 min, t-butyl acetate then 08C and acetic acid; (iii) CuBr2, hydroxy(tosyloxy)iodobenzene, CH3CN, 08C, 5 min; (iv) comp. 3, K2CO3, Bu4NBr,
CH3CN, 24 h, rt; (v) BF3·Et2O, CH2Cl2.
Scheme 4. Reagents and conditions: (i) CH2Br2, MeLi, THF, 2788C; (ii) AcONa, DMF, 2 h, rt; (iii) MePPhþ3 I2, THF, BuLi, 2788C; (iv) K2CO3, MeOH, 3 h,
rt; (v) imidazole, Ph3P·Br2, CH2Cl2, 10 min, 08C.

Z. Kałuz˙a et al. / Tetrahedron 59 (2003) 5893–5903
5895
Scheme 5. Reagents and conditions: (i) Bu4NþHSO42, BuLi, THF, 30 min at 2788C then gradually to rt; (ii) various Levis acids and conditions, see Table 1;
(iii) CH2Cl2/MeOH, O3, 10 min at 2788C then Me2S; (iv) PCC/silica gel, CH2Cl2, 6 h, reflux.
substrate should not influence the stereoselectivity of
cyclization. We expected that the major compound should
have the (R)-configuration at C-6 (Scheme 1). Unfortu-
nately, the mixture of 15 when treated with the BF3·Et2O
underwent decomposition, probably due to the instability of
either the easy enolizable substrate 15 or product 16, under
the reaction conditions. This assumption led us to revise our
original plan and to propose use of compound 22, lacking, in
comparison to the 15, the t-butyloxycarbonyl group.
the presence of BF3·Et2O did not furnish the expected
oxacephams 23, 24 and only tarry products were obtained.
The well-documented examples of the synthesis of
oxacephems or oxacephams with an exocyclic C-3
methylene substituent via acid-catalyzed nucleophilic
substitution at the b-lactam C-4 carbon, allowed us to
expect that replacement of the carbonyl group in the side
chain by a double bond should provide Lewis acid-stable
substrates (and products, as well).4 In particular, the
literature example4 directed our attention to a new substrate
25, that should be suitable for cyclization. The compound 25
was obtained by a standard reaction sequence. The
bromoketone 17 was transformed into the acetate 18,
which was subsequently subjected to a Wittig olefination
(Scheme 4). The crude olefin 19 was hydrolyzed to give
allyl alcohol 20. The bromination of 20 with triphenyl-
phosphine dibromide in a presence of imidazole yielded 21.
The alkylation of 3 with the bromide 21 provided 25 as an
equimolar mixture of diastereomers in 79% yield
(Scheme 5). The vinyloxy group in 25 was oxidized with
PCC on silica gel to give a mixture of respective 4-acetates
29 in 72% yield. The acetate 29 was accompanied by a
The bromoketone 17 was prepared from lactate 11 in 88%
yield, employing the one-step general procedure
(Scheme 4).17 The alkylation of 3 with 17 under the PTC
conditions (K2CO3, Bu4NBr, acetonitrile), or in the
presence of common bases such as triethylamine, DBU or
diisopropylethylamine failed. Fortunately, treatment of an
equimolar mixture of b-lactam 3 and tetrabutylammonium
hydrogen sulfate with two equivalents of butyllithium in
THF at 2788C, followed by the addition of 17 in one
portion, resulted in the formation of the N-alkylated product
22 in 20% yield (Scheme 5).
The isolated compound 22, during attempted cyclization in
Table 1. Catalysts and reaction conditions of cyclizations of 25, 29 and 31.
Substrate
Lewis acid
Amount (equiv.)
Reaction time, temperature (8C)
Yield of 27 and 28 (%)
dr 27:28
By-products and comments
25
BF3·Et2O
SnCl2
1
1
15 min; rt
50 min; rt
30
20
4:1
9:1
TMS-Cl
SnCl4 0.5
SnCl4
SnCl4
TiCl4
BF3·Et2O
SnCl2
TMS-Cl
SnCl4
TiCl4
4
0.5
1
1
1
1
1
4
0.5
1
50 min; rt
2.5 h; rt
10 min; 245
5 min; 0
1.5 h; 0
14
50
2.8:1
4:1
26 (12%)
29
31
31 (60%)
31 (52%)
50
50
4:1
8.8:1
50 min; rt
20 min; rt
12 h; rt
30 min; rt
50
20
9:1
7:1
Decomposition
BF3·Et2O
1

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Z. Kałuz˙a et al. / Tetrahedron 59 (2003) 5893–5903
presence of SnCl4 gave a mixture of acetals 26 together with
cephams 27 and 28. The acetate 29 treated with an
equimolar amount of SnCl4 or TiCl4 formed the correspond-
ing complexes immediately, which in the presence of
moisture underwent subsequent debenzylation to provide
alcohol 31. The effective cyclization required about 1 h but
did not proceed beyond approx. 50% conversion. The best
yield and selectivity were obtained for the acetate 29 and
SnCl2/TMS-Cl mixture. As we expected, in all cases the
desired diastereomer (6R)-27 prevails. The configurations of
both diastereomers 27 and 28 were assigned by analysis and
comparison of respective NOEs (Fig. 1). The assignments
made by 1H NMR were corroborated by the X-ray structure
analysis made for 28 (Fig. 2).18 Since the isomers 27 and 28
were not easy to separate, for the next step they were used as
a mixture.
Figure 1. The NOE effects in 1H NMR spectra of 27 and 28.
The double bonds in 27 and 28 can be easily oxidized to the
carbonyl groups providing ketones 23 and 24, respectively.
The compounds 23 and 24 were separated into the pure
individual components that offer a convenient starting point
for further transformations leading to the substituted 5-
oxacephems. The structure and configuration of 23 was
proved by the X-ray structure analysis (Fig. 3).18
It was of interest to compare the results found for
cyclization of 25, 29 and 31 with the corresponding
reactions leading to their congeners that are not chiral:
unsubstituted at C-4 43 and 44, and 4,4-dimethyl substituted
46 and 47. As a starting material, ether 3319 and alcohol 3720
were selected. Both compounds 33 and 37 were transformed
into the respective bromo-ethers 36 and 41 using a standard
reaction sequence (Scheme 6).
Figure 2. ORTEP diagram of compound 28.
The N-alkylation of 3 with 36 and 41 gave compounds 42
and 45 (Scheme 7). The b-lactam 42 treated with BF3·Et2O
afforded oxacepham 43 in 50% yield. The cyclization of 45,
however, was not successful under those conditions. The
successful formation of oxacepham 46 required prior
oxidation of the vinyloxy group to the acetate 48, which
was subjected to the cyclization in the presence of BF3·Et2O
to give 46 in 50% yield. When the 48 was treated with
SnCl2/TMS-Cl, the product 46 was obtained in 20% yield
only and it was accompanied by 30% of chloride 49.
Ozonolysis of 43 and 46 led to corresponding ketones 44
and 47 in a good yield. Compounds 50 and 51, which are
related to the ketone 44, have recently been obtained (in a
7:3 ratio) by us from glyceraldehyde using three other
methodologies.11
Figure 3. ORTEP diagram of compound 23.
minute amount of a ketone 30. The compounds 25 and 29
were subjected to the cyclization in the presence of a Lewis
acid.
Table 1 shows that the 4-acetoxy group reacts more readily
than the 4-vinyloxy one. Moreover, the compound 25 in the
It was shown that 5-oxacephams with an 3-exo-methylene
Scheme 6. Reagents and conditions: (i) PMB-OH, NaH, DMF, 1 h rt; (ii) LiClO4, pyridine, SO2Cl2, CH2Cl2, 10 min at 2788C; (iii) THF/H2O, K2CO3, reflux,
6 h; (iv) imidazole, Ph3P·Br2, CH2Cl2, 10 min 08C; (v) PMB-Cl, NaH, DMF, 408C.

Z. Kałuz˙a et al. / Tetrahedron 59 (2003) 5893–5903
5897
Scheme 7. Reagents and conditions: (i) Bu4NþHSO24 , BuLi, THF, 2788C gradually to 08C; (ii) BF3·Et2O, CH2Cl2; (iii) CH2Cl2/MeOH, O3, 10 min at 2788C
then Me2S; (iv) PCC/silica gel, CH2Cl2 6 h, reflux; (v) SnCl2, TMS-Cl, CH2Cl2.
group or a 3-carbonyl group (suitable for further
functionalization) can be easily obtained starting from
4-vinyloxy-azetidin-2-one 3. The introduction of a methyl
group to C-4 of the cepham skeleton with good stereo-
selectivity can be performed using ethyl lactate 9 as a chiral
starting material.
The reaction mixture was stirred vigorously for 15 min, and
the (S) ethyl 2-(p-methoxybenzyloxy)-propionate 11 (1.2 g,
5 mmol) was added. The temperature was allowed to rise to
room temperature then the mixture was cooled to 08C and
acetic acid (0.72 g) was added dropwise. Subsequently, the
reaction mixture was diluted with t-BuOMe (80 mL),
washed with saturated NaHCO3 aq. solution (80 mL),
brine (80 mL), dried and evaporated. The crude product
was purified by chromatography using t-BuOMe/hexane/
toluene (3:17:80 v/v/v) as an eluant to give 12 (1.47 g;
96%). Oil; [a]D¼26.2 (c 0.92, CH2Cl2); IR (film) 1742,
1. Experimental
1.1. General
1
1716, 1514, 1456, 1249 cm21; H NMR (CDCl3): 1.34 (d,
3H, J¼6.5 Hz, CH3), 1.45 (bs, 9H, t-Bu), 3.51 (s, 2H, H-
2,2), 3.81 (s, 3H, OMe), 3.99 (q, 1H, J¼6.5 Hz, H-4), 4.49
(bs, 2H, Bn), 7.27, 6.89 (2m, 4H, Aryl); 13C NMR d 16.8,
27.9, 45.8 (t), 55.3, 71.6 (t), 79.9, 81.8 (s), 113.8, 129.1 (s),
129.6, 159.5 (s), 166.6 (s), 205.8 (s); MS (HR-ESI) m/z:
(MþNa)þ requires for C17H24O5Na: 331.1516. Found:
331.1528; Anal. calcd for C17H24O5 (308.37): C, 66.21;
H, 7.84. Found: C, 66.08; H, 7.67.
The melting points are uncorrected. The optical rotations
were measured using JASCO Dip-360 and P-1020 digital
polarimeters. The IR spectra were obtained using FT-IR-
1
1600 Perkin–Elmer spectrophotometer. The H NMR and
13C NMR spectra were recorded using Bruker AM 500
spectrometer. The mass spectra were recorded using AMD
604 mass spectrometer. The column chromatography was
performed on Merck Kiesel gel (230–400 mesh). The
ozonolysis was carried out using Buchi Ozone Generator
OZI.
1.1.3. (2R,4S) and (2S,4S) tert-Butyl 2-bromo-4-(p-
methoxybenzyloxy)-3-oxo-pentanoates (13) and (4S)
tert-butyl 2,2-dibromo-4-(p-methoxybenzyloxy)-3-oxo-
pentanoate (14). To the vigorously stirred solution of
compound 12 (7.7 g, 25 mmol) in acetonitrile (250 mL), at
08C, the copper (II) bromide (7.26 g, 35.5 mmol), and
hydroxy(tosyloxy)iodobenzene (9.8 g, 25 mmol) was added
and the mixture was stirred at 08C for 5 min. Subsequently,
it was poured into cold water, extracted with CH2Cl2, dried,
and concentrated. The crude products were purified by flash
chromatography using toluene/AcOEt (97:3 v/v) as an
eluant to give 13 (3.57 g, 37%) and 14 (3.96 g, 34%).
All reactions were carried out under argon atmosphere using
anhydrous solvents. The reagents were purchased from
commercial supplies and used without further purification,
unless noted. The tetrahydrofuran was distilled from Na and
benzophenone ketyl, the ethylene chloride and toluene were
distilled from CaH2.
1.1.1. (2S) Ethyl 2-(p-methoxybenzyloxy)-propanoate
(11). The compound 11 was obtained according to Shimano
et al.13 procedure.
1H NMR spectrum of a crude mixture shows compounds 12,
13 and 14 in a ratio 1:9:1.
1.1.2. (4S) tert-Butyl 4-(p-methoxybenzyloxy)-3-oxo-pen-
tanoate (12). To a solution of HMDS-Li (12 mL 1 M
solution in hexane, 12 mmol) in THF (40 mL), at 2508C,
the tert-butyl acetate (1.4 g, 12 mmol) was added dropwise.
Compound 13. Oil; IR (film) 1731, 1613, 1514, 1370,

5898
Z. Kałuz˙a et al. / Tetrahedron 59 (2003) 5893–5903
1
1249 cm21; H NMR (selected signals for the mixture of
diastereomers; CDCl3): 1.52–1.33 (m, 24H, t-Bu and H-5),
3.81 (bs, 6H, OMe), 4.32–4.13 (m, 2H, H-4), 4.61–4.43 (m,
4H, Bn), 5.27, 5.22 (2s, 2H, H-2), 7.27, 6.88 (2 m, 8H,
Aryl); Anal. calcd for C17H23BrO5 (387.27): C, 66.21; H,
7.84. Found: C, 66.08; H, 7.67.
1.1.6. (3S) 1-Acetoxy-3-(p-methoxybenzyloxy)-butan-2-
one (18). To a solution of compound 17 (1.44 g, 5 mmol) in
DMF (20 mL), the AcONa (2 g, 25 mmol) was added and
the mixture was stirred at room temperature for 2 h.
Subsequently, it was poured into cold water, extracted
with t-BuOMe, dried, and concentrated. The crude product
was purified by chromatography using hexane/t-BuOMe
(70:30 v/v) as an eluant to give 18 (7.2 g; 82 %). Oil;
Compound 14. Mp 53–548C; IR (CH2Cl2) 1761, 1742,
1515, 1248 cm21; H NMR (CDCl3): 1.34 (s, 9H, t-Bu),
1.41 (d, 3H, J¼6.6 Hz, CH3), 3.81 (s, 3H, OMe), 4.62–4.43
(m, 3H, H-4, Bn), 7.28, 6.86 (2 m, 4H, Aryl); Anal. calcd for
C17H22 Br2O5 (466.16): C, 43.80; Br, 34.28; H, 4.76. Found:
C, 42.59; Br, 34.42; H, 4.85.
1
[a]D¼210.2 (c 0.59, CH2Cl2); IR (film) 1738, 1752 cm21
;
1H NMR (CDCl3): 1.37 (d, 3H, J¼6.8 Hz, CH3), 2.16 (s,
3H, Ac), 3.81 (s, 3H, OMe), 4.03 (q, 1H, J¼6.8 Hz, H-3),
4.49, 4.54 (2d, 2H, J¼11.3 Hz, Bn), 4.91, 4.97 (2d, 2H,
J¼17.6 Hz, H-1), 6.89, 7.27 (2 m, 4H, Aryl); 13C NMR d
17.0, 20.4, 55.3, 65.9 (t), 71.6 (t), 79.1, 114, 129.2 (s), 129.5,
159.5 (s), 170.3 (s), 205.2 (s); MS (HR-LSIMS) m/z:
(MþNa)þ requires for C14H18O5Na: 289.1052. Found:
289.1054; Anal. calcd for C14H18O5 (266.29): C, 63.15;
H, 6.81. Found: C, 63.25; H, 6.75.
1.1.4. (2R,4S,40R), (2R,4S,40S), (2S,4S,40R), (2S,4S,40S)
tert-Butyl 4-(p-methoxybenzyloxy)-3-oxo-2-(40-vinyloxy-
azetidin-20-on-10-yl)-pentanoates (15). To a stirred suspen-
sion of K2CO3 (1.66 g, 12 mmol) and Bu4NBr (0.65 g,
2 mmol) in CH3CN (10 mL), the crude compound 13
(0.93 g, 2.4 mmol) and 4-vinyloxy-azetidin-2-one (0.22 g,
1.9 mmol) were added. The mixture was stirred at room
temperature for 24 h. Subsequently, it was diluted with
toluene (10 mL), the precipitate was filtered off, the filtrate
was poured into water (50 mL), extracted with toluene
(3£20 mL), dried, and evaporated. The crude product was
purified by flash chromatography using hexane/t-BuOMe
(75:25 v/v) as an eluant to afford a mixture of two
diastereomers (0.42 g, 52%). Oil; IR (CH2Cl2) 1780,
1.1.7. (3S) 2-Hydroxymethyl-3-(p-methoxybenzyloxy)-
but-1-ene (20). To a stirred suspension of finely pulverized
methyltriphenylphosphonium iodide (12.4 g, 30.6 mmol) in
THF (250 mL), at 2788C, BuLi (15.3 mL 2 M solution in
cyclohexane, 30.6 mmol) was added dropwise. The tem-
perature was allowed to rise until the mixture became clear
(about 08C). The mixture was cooled again to 2788C and
treated with 18 (7 g, 26.5 mmol). The temperature was
allowed to rise to room temperature and the mixture was
stirred for 0.5 h. Subsequently it was diluted with t-BuOMe
(100 mL), filtered through Celite and concentrated. The
crude 19 was dissolved in MeOH (200 mL), catalytic
amount of K2CO3 was added and the mixture was stirred at
room temperature for 3 h. Subsequently it was filtered
through Celite and concentrated. The crude product was
purified by chromatography using hexane/AcOEt (70:30
v/v) as an eluant to give 20 (4.3 g; 73 %). Oil; [a]D¼229.9
(c 0.59, CH2Cl2); IR (CH2Cl2) 3512, 1613, 1514 cm21; 1H
NMR (CDCl3): 1.34 (d, 3H, J¼6.6 Hz, CH3), 3.79 (s, 3H,
OMe), 4.08 (q, 1H, J¼6.5 Hz, H-3), 4.15, 4.26 (2d, 2H,
J¼13.5 Hz, CH2OH), 4.34, 4.47 (2d, 2H, J¼11.3 Hz, Bn),
5.11, 5.20 (2bs, 2H, vCH2a,b); 13C NMR d 20.2, 55.2, 63.1
(t), 69.9 (t), 77.1, 112.6 (t), 113.8, 129.3, 130.4 (s), 148.8 (s),
159.2 (s); MS (HR-EI) m/z: Mþ requires for C13H18O3:
222.1256. Found: 222.1266; Anal. calcd for C13H18O3
(222.28): C, 70.24; H, 8.16. Found: C, 69.88; H, 8.18.
1740, 1613, 1514, 1371 cm21; H NMR (selected signals
1
for the mixture of two diastereomers in a ratio of about
2.3:1): major component 1.30 (d, J¼6.5 Hz, Me), 1.48 (s,
t-Bu), 2.87 (dd, J¼15.2, 1.6 Hz, H-3a), 3.03 (dd, J¼15.2,
4.2 Hz, H-3b), 3.80 (s, OMe), 5.61 (dd, 1H, J¼4.2, 1.6 Hz,
H-4), 6.46 (dd, 1H, J¼14.1, 6.5 Hz, vCH–O); minor
component 1.35 (d, J¼6.5 Hz, Me), 1.47 (s, t-Bu), 2.88
(dd, J¼15.2, 1.7 Hz, H-3a), 3.06 (dd, J¼15.2, 4.3 Hz,
H-3b), 3.79 (s, OMe), 5.57 (dd, 1H, J¼4.3, 1.7 Hz, H-4),
6.456 (dd, 1H, J¼14.1, 6.6 Hz, vCH–O); MS (EI-HR) m/z:
(MþNa)þ requires for C22H29O7NaN: 442.1842. Found:
442.1838.
1.1.5. (3S) 1-Bromo-3-(p-methoxybenzyloxy)-butan-2-
one (17). To a stirred solution of compound 11 (2.4 g,
10 mmol) and CH2Br2 (3.45 g, 1.39 mL, 20 mmol) in THF
(40 mL) upon cooling to 2788C, MeLi (20 mL, 1 M
solution in THF/cumene 1:9, 20 mmol) was added drop-
wise. Stirring and cooling was continued for 30 min and
then acetic acid (2.4 g, 2.3 mL, 40 mmol) was added. The
temperature was allowed to rise to 08C. The solution was
poured into an ice-water mixture (,150 mL), extracted with
t-BuOMe (3£50 mL), extracts were dried over MgSO4 and
evaporated. The product was purified by chromatography
using hexane/AcOEt (85:15 v/v) as an eluant to give 17
(2.5 g; 88 %). Oil; [a]D¼215.4 (c 1, CH2Cl2); IR (CH2Cl2)
1.1.8. (3S) 2-Bromomethyl-3-(p-methoxybenzyloxy)-but-
1-ene (21). To a solution of imidazole (1.52 g, 22.4 mmol)
in CH2Cl2 (120 mL) the compound 20 (4.14 g, 18.64 mmol)
was added and the mixture was cooled to 08C. Separately,
the Ph3P (5.37 g, 20.5 mmol) and bromine (3.28 g; 1 mL,
20.5 mmol) were added to CH2Cl2 (70 mL) at 08C. The
resulted suspension was added via cannula to the solution
containing compound 20. The mixture was stirred at 08C for
10 min. Subsequently, it was poured into an ice-water
mixture and extracted with t-BuOMe. The extract was dried
over MgSO4 and concentrated. The crude product was
purified by chromatography using hexane/t-BuOMe (94:6
v/v) as an eluant to give 21 (4.4 g; 83 %). Oil; [a]D¼230.0
(c 0.66, CH2Cl2); IR (CH2Cl2) 1613, 1514 cm21; 1H NMR
(CDCl3): 1.35 (d, 3H, J¼6.5 Hz, CH3), 3.80 (s, 3H, OMe),
3.97, 4.07 (2d, 2H, J¼10.6 Hz, CH2OH), 4.16 (q, 1H,
J¼6.4, H-3), 4.47, 4.32 (2d, 2H, J¼11.3, Bn), 5.33, 5.39
1737 cm21
;
1H NMR (CDCl3): 1.39 (d, 3H, J¼6.8 Hz,
CH3), 3.81 (s, 3H, OMe), 4.15 (bs, 2H, CH2Br), 4.17 (q, 1H,
J¼6.8 Hz, H-3), 4.49, 4.54 (2d, 2H, J¼11.3 Hz, Bn), 6.89,
7.27 (2 m, 4H, Aryl); 13C NMR d 17.2, 31.8 (t), 55.3, 71.8
(t), 78.6, 114.0, 129.1 (s), 129.6, 159.6 (s), 203.3 (s); MS
(HR-LSIMS) m/z: (MþNa)þ requires for C12H15O739BrNa:
309.0107. Found: 309.0102; Anal. calcd for C12H15BrO3
(287.15): C, 50.19; H, 5.26; Br, 27.83. Found: C, 50.33; H,
5.35; Br, 27.78.

Z. Kałuz˙a et al. / Tetrahedron 59 (2003) 5893–5903
5899
(2bs, 2H, vCH2), 6.88, 7.27 (2 m, 4H, Aryl); 13C NMR d
20.5, 32.2 (t), 55.3, 70.1 (t), 75.2, 113.8, 116.6 (t), 129.3,
130.5 (s), 146.6 (s), 159.2 (s); MS (HR-EI) m/z: Mþ requires
for C13H17O729Br: 284.0412. Found: 284.0414; Anal. calcd
for C13H17BrO2 (285.18): C, 54.75; H, 6.01; Br, 28.02.
Found: C, 54.61; H, 6.00; Br, 28.12.
was added. The suspension was stirred under reflux for 6 h,
then filtered through Celite. The Celite pad was washed
several times with AcOEt and the combined filtrates were
concentrated. The crude product was purified by chroma-
tography using hexane/AcOEt (60:40 v/v) as an eluant to
give 29 (250 mg; 72 %) and 30 (35 mg, 10%).
1.1.9. (4R,30S) and (4S,30S) 1-[30-(p-Methoxybenzyloxy)-
20-oxo-butyl]-4-vinyloxy-azetidin-2-one (22). To a stirred
suspension of finely powdered tetrabutylammonium hydro-
gen sulfate (390 mg, 1.1 mmol) in THF (15 mL) was added
4-vinyloxy-azetidin-2-one (113 mg, 1.0 mmol). Upon cool-
ing to 2788C, BuLi (1.1 mL, 2 M solution in cyclohexane,
2.2 mmol) was added. The temperature was allowed to rise
until the mixture became clear (about 2308C). Sub-
sequently, it was cooled again to 2788C and treated with
17 (290 mg, 1.0 mmol). After 30 min the temperature was
allowed to rise 08C and the mixture was poured into cold
water containing citric acid and extracted with AcOEt. The
extract was dried and concentrated. The crude product was
purified by chromatography using AcOEt/hexane (40:60
v/v) as an eluant to give 22 (63 mg; 20%). Oil; [a]D¼211.2
(c 0.96, CH2Cl2); IR (CH2Cl2) 1774, 1731 cm21; 1H NMR
(selected signals for two diastereomers in a ratio 1:1;
CDCl3): 1.38 (d, 3H, J¼6.8 Hz, Me), 3.27, 3.29 (2dd, 2H,
J¼15.0, 3.8 Hz, H-3), 3.81 (2s, 3H, OMe), 3.98, 3.99 (2q,
2H, J¼6.8 Hz, H-30), 4.16, 4.17 (2dd, 1H, J¼6.7, 2.0 Hz,
OCHvCHH), 4.33, 4.35 (2dd, 1H, J¼14.3, 2.0 Hz,
OCHvCHH), 5.54, 5.56 (2dd, 2H, J¼1.2, 3.8 Hz, H-4),
6.34, 6.37 (dd, 2H, J¼14.3, 6.7 Hz, OCHvCH2); MS (HR-
LSIMS) m/z: (MþH)þ requires for C17H22O5N: 320.1498.
Found: 320.1489; Anal. calcd for C17H21NO5 (319.35): C,
63.94; H, 6.63. Found: C, 63.73; H, 6.93.
Compound 29. Oil; [a]D¼226.8 (c 1.0, CH2Cl2); IR
(CH2Cl2) 1772, 1752 cm21 1H NMR (selected signals
;
taken for the mixture of diastereomers in a ratio of about
1:1; CDCl3): 1.31, 1.30 (2d, 3H, J¼6.5 Hz, CH3), 2.06, 2.07
(2s, 3H, Ac), 2.95, 2.96 (2bd, 1H, J¼15.0 Hz, H-3), 3.23
(dd, 1H, J¼15.0, 3.8 Hz, H-3), 3.80 (s, 3H, OMe), 5.08,
5.09, 5.17, 5.18 (4bs, 2H, vCH2), 6.01, 6.02 (2dd, 1H,
J¼3.8, 1.2 Hz, H-4); MS (HR-LSIMS) m/z: (MþH)þ
requires for C18H24NO5: 334.1654. Found: 334.1654;
Anal. calcd for: C18H23NO5 (333.38): C, 64.85; H, 6.95;
N, 4.20. Found: C, 64.89; H, 6.78; N, 4.30.
Compound 30. Oil; IR (CH2Cl2) 1774, 1753, 1680 cm21; 1H
NMR (CDCl3): 2.09 (s, 3H, Ac), 2.36 (s, 3H, CH3), 2.94 (bd,
1H, J¼15.0 Hz, H-3), 3.27 (dd, 1H, J¼15.0, 3.9 Hz, H-30),
4.08, 4.02 (2d, 2H, J¼16.3 Hz, NCH2), 5.98 (dd, 2H, J¼3.9,
1.2 Hz, H-4), 6.00, 6.17 (2bs, 2H, vCH2); 13C NMR d 20.8
(t), 25.7 (t), 41.4, 44.9, 76.6 (t), 126.9, 143.0 (s), 165.5 (s),
170.5 (s), 198.1 (s); MS (HR-LSIMS) m/z: (MþH)þ
requires for C10H14NO4: 212.0923. Found: 212.0924;
Anal. calcd for: C10H13NO4 (211.22): C, 56.87; H, 6.20;
N, 6.63. Found: C, 56.73; H, 6.17; N, 6.78.
1.2. General procedure for preparation of 5-oxacephams
27 and 28 (see Table 1). To a stirred solution of
N-substituted b-lactam (25, 29 or 31, 0.3 mmol) in dry
CH2Cl2 (3 mL) the Lewis acid was added. The mixture was
stirred until disappearance of the substrate (TLC monitor-
ing). The saturated solution of NaHCO3 (2 mL) was added
and stirring was continued for 10 min. The organic phase
was separated, dried (MgSO4) and evaporated. The
analytical samples of pure diastereoisomers 27 and 28
were obtained using HPLC (t-BuOMe/hexane 40:60). For
the subsequent synthesis of 23 and 24 a crude mixture of 27
and 28 was used.
1.1.10. (4R,30S) and (4S,30S) 1-[30-(4-methoxy-benzyl-
oxy)-20-methylene-butyl]-4-vinyloxy-azetidin-2-one (25).
Compound 25 was prepared from 21 (280 mg, 1.0 mmol)
and 4-vinyloxy-azetidin-2-one (135 mg, 1.2 mmol) accord-
ing to the procedure described for 22. The crude product
was purified by chromatography using AcOEt/hexane
(40:60 v/v) as an eluant to give 25, (250 mg, 79%). Oil;
[a]D¼217.6 (c 0.65, CH2Cl2); IR (CH2Cl2) 1768 cm21; 1H
NMR (selected signals taken from the mixture of two
diastereomers in a ratio of about 1:1; CDCl3): 1.31, 1.30 (2d,
3H, J¼6.5 Hz, Me), 2.89, 2.90 (2bd, 2H, J¼14.9 Hz H-3),
3.10, 3.11 (2dd, 2H, J¼14.9, 3.7 Hz, H-3), 3.73, 3.75 (2d, H,
J¼16.6 Hz, NCHH), 3.97, 4.00 (2q, 1H, J¼6.5 Hz, H-30),
4.04 (d, 1H, J¼16.6, NCHH), 4.17 (2dd, 1H, J¼6.7, 2.0 Hz,
OCHvCHH), 4.34 (2dd, 1H, J¼14.3, 2.0 Hz,
OCHvCHH), 4.41, 4.44 (2d, 2H, J¼11.0 Hz, Bn), 5.10,
5.12 (2d, 1H, J¼1.2 Hz, vCHH), 5.20, 5.23 (2 bs, 1H,
vCHH), 5.25 (2dd, 2H, J¼3.7, 1.2 Hz, H-4), 6.35, 6.36
(2dd, 1H, J¼14.3, 6.7 Hz, OCHvCH2); MS (HR-LSIMS)
m/z: (MþNa)þ requires for C18H23O4NaN: 340.1525.
Found: 340.1524; Anal. calcd for: C18H23NO4 (319.36):
C, 68.12; H, 7.3; N, 4.41. Found: C, 68.14; H, 7.21; N, 4.38.
1.2.1. (4S,6R) 4-Methyl-3-methylene-5-oxa-cepham (27).
Mp 52–538C; [a]D¼þ100.8 (c 0.51, CH2Cl2); IR (CH2Cl2)
1765 cm21; 1H NMR (CDCl3): 1.42 (d, 3H, J¼6.3 Hz, Me),
2.80 (dd, 1H, J¼0 14.9, 0.7 Hz, H-7), 3.16 (ddd, 1H, J¼15.0,
3.3, 1.9 Hz, H-7 ), 3.63 (dd, 1H, J¼15.0, 1.9 Hz, H-2), 4.18
(bq, 1H, J¼6.3 Hz, H-4), 4.32 (bd, 1H, J¼15.0 Hz, H-20),
5.01, 5.06 (2 m, 2H, CvCH2), 5.10 (dd, 1H, J¼3.3, 0.7 Hz,
H-6);); 13C NMR d 17.5, 44.6 (t), 45.5 (t), 72.6, 77.6, 110.7
(t), 139.7 (s), 167.5 (s); MS (EI-HR) m/z: Mþ requires for
C8H11NO2: 153.0790. Found: 153.0793; Anal. calcd for
C8H11NO2 (153.18): C, 62.73; H, 7.24; N, 9.14. Found: C,
62.72; H, 7.20; N, 9.08.
1.2.2. (4S,6S) 4-Methyl-3-methylene-5-oxa-cepham (28).
Mp 758C; [a]D¼2248.8 (c 0.18, CH2Cl2); IR (CH2Cl2)
1763 cm21; 1H NMR (CDCl3): 1.41 (d, 3H, J¼6.9 Hz, Me),
2.75 (bd, 1H, J¼15.0 Hz, H-7), 3.11 (ddd, 1H, J¼15.0, 3.2,
1.8 Hz, H-70), 3.72 (dd, 1H, J¼15.5, 1.8 Hz, H-2), 4.24 (bd,
1H, J¼15.5 Hz, H-20), 4.47 (q, 1H, J¼6.9 Hz, H-4), 4.93,
4.88 (2bs, 2H, vCH2), 5.16 (d, 1H, J¼3.2 Hz, H-6).
1.1.11. (4R,30S) and (4S,30S) 1-[30-(p-Methoxy-benzyl-
oxy)-20-methylene-butyl]-4-acetoxy-azetidin-2-one (29)
and (4R), and (4S) 1-[20-methylene-but-30-one-10-yl]-4-
acetoxy-azetidin-2-one (30). To a solution of compound 25
(340 mg, 1 mmol) in CH2Cl2 (30 mL) the mixture of PCC
(650 mg, 3 mmol) and silica gel (800 mg Merck Kiesel gel)

5900
Z. Kałuz˙a et al. / Tetrahedron 59 (2003) 5893–5903
1.2.3. (4S) 1-Aza-3-methylene-4,6-dimethyl-5,7-dioxa-
bicyclo[6.2.0]decan-8-ones (26). Compound 26 was
obtained from 25 in the presence SnCl4 (0.5 equiv.) in a
12% yield, as a by-product during preparation of 5-oxa-
cephams 27 and 28 (see Table 1).
Me), 3.11 (dd, 1H, J¼16.0, 0.9 Hz, H-7), 3.36 (ddd, 1H,
J¼16.0, 3.3, 1.6 Hz, H-70), 3.72 (ddd, 1H, J¼19.2, 1.6,
0.9 Hz, H-2), 4.38 (bq, 1H, J¼6.7 Hz, H-4), 4.43 (d, 1H,
J¼19.2 Hz, H-20), 5.41 (d, 1H, J¼3.3 Hz, H-6);); 13C NMR
d 14.3, 44.53 (t), 48.9 (t), 72.6, 76.1, 169.7 (s), 202.9 (s); MS
(EI-HR) m/z: Mþ requires for C7H9NO3: 155.0582. Found:
155.0572.
Compound 26. Oil; [a]D¼þ5.5 (c 0.4, CH2Cl2); IR
1
(CH2Cl2) 1757 cm21; H NMR (selected signals taken for
the mixture of diastereomers; CDCl3): 1.32, 1.33, 1.41, 1.42
(4d, 6H, C4-Me and C6-Me), 2.62, 2.87 (2bd, 1H,
J¼14.7 Hz, H-9), 4.33, 4.56 (2bq, 1H, H-4), 4.92, 4.98,
5.29 (3dd, 1H, H-6); MS (EI-HR) m/z: (M)þ requires for
C10H15NO3: 197.1052. Found: 197.1021.
1.3.3. 3-(p-Methoxybenzyloxy)-2-methyl-prop-1-ene
(33). The compound 33 was obtained according to Wallace
et al.19 procedure.
1.3.4. 2-Chloromethyl-3-(p-methoxybenzyloxy)-prop-1-
ene (34). To the solution of compound 33 (87 mg,
0.45 mmol) in CH2Cl2 (5 mL), LiClO4 (9.5 mg,
0.09 mmol) and pyridine (43 mg, 44 mL, 0.54 mmol) was
added. The mixture was cooled to 2788C and sulfuryl
chloride (72.9 mg, 44 mL, 0.54 mmol) was added. Stirring
and cooling was continued for 10 min, then the temperature
was allowed to rise to 08C. The mixture was poured into
cold water containing NaHCO3, extracted with hexane and
extract was dried and concentrated. The crude product was
purified by chromatography using hexane/t-BuOMe (95:5
v/v) as an eluant to give 34 (41 mg, 40%). Oil; IR (CH2Cl2)
1.2.4. (4R,30S) i (4S,30S) 4-Acetoxy-1-[30-hydroxy-20-
methylene-but-10-yl]-azetidin-2-one (31). The compound
31 was obtained from 29 in the presence SnCl4 or TiCl4
(1 equiv. in each case) in 60% and 52% respectively, if the
reaction time was 10 and 5 min, respectively (Table 1). Oil;
[a]D¼224.2 (c 1.58, CH2Cl2); IR (CH2Cl2) 1771,
1751 cm21 1H NMR (taken for the mixture of dia-
;
stereomers; CDCl3þD2O): 1.31, 1.32 (2d, 3H, J¼6.5 Hz,
CH3), 2.09 (s, 3H, Ac), 2.98 (bd, 1H, J¼15.0 Hz, H-3a), 3.27
(dd, 1H, J¼15.0, 4.0 Hz, H-3b), 3.92, 3.91 (2dd, 2H,
J¼16.0 Hz, NCH2), 4.30, 4.32 (2q, 1H, J¼6.6 Hz, H-30),
6.00, 6.02 (2dd, 1H, H-4); MS (HR-LSIMS) m/z: (MþH)þ
requires for C10H16NO4: 214.1079. Found: 214.1089; Anal.
calcd for C10H15NO4 (213.23): C, 56.33; H, 7.09; N, 6.57.
Found: C, 56.12; H, 7.10; N, 6.67.
1
2960, 1613 cm21; H NMR (CDCl3): 3.81 (s, 3H, OMe),
4.09 (bs, 2H, CH2Cl), 4.12 (bs, 2H, Bn), 4.45 (s, 2H,
CH2OPMB), 5.25, 5.31 (2 m, 2H, vCH2), 6.88, 7.26 (2 m,
4H, Aryl); 13C NMR d 45.3 (t), 55.3 (q), 70.0 (t), 72.1 (t),
113.8 (d), 116.7 (t), 129.3 (d), 130.1 (s), 142.1 (s), 159.3 (s);
MS (HR-ESI) m/z: (MþNa)þ requires for C12H15O2Na35Cl:
249.0653. Found: 249.0670; Anal. calcd for C12H15ClO2
(226.70): C, 63.58; H, 6.67; Cl, 15.64. Found: C, 62.57; H,
6.97.
1.3. Preparation of compounds 23 and 24
The solution of diastereoisomers 27 and 28 (92 mg,
0.6 mmol) in CH2Cl2 (20 mL) and methanol (1 mL) was
placed in a three-necked flask, equipped with thermometer,
bubbling tube and ozone outlet. The solution was stirred and
upon cooling to 2788C ozone was bubbled in. After about
10 min, the TLC showed the disappearance of the substrate,
and the solution turned light-blue. The ozone generation
was turned off, and oxygen was passed through the solution
for 5 min to remove the excess of ozone. Subsequently,
dimethyl sulfide (0.4 mL) was added in one portion, and
stirring was continued at 2788C for 10 min. The reaction
mixture was brought to room temperature and solvent
evaporated. Purification on silica gel using AcOEt/hexane
(60:40 v/v) as an eluant gave 23 and 24 in 85% yield. The
ratio of diastereomers 23 and 24 depended on the
corresponding ratio of the substrate 27/28.
1.3.5. 2-Hydroxymethyl-3-(p-methoxybenzyloxy)-prop-
1-ene (35). To the solution of compound 34 (88 mg,
0.39 mmol) in THF (5 mL), water (20 mL) and K2CO3
(110 mg, 0.78 mmol) were added. The mixture was heated
under reflux until the substrate has disappeared (,6 h).
After cooling, the mixture was extracted with AcOEt
(3£10 mL), dried and concentrated. The crude product
was purified by chromatography using hexane/t-BuOMe
(50:50 v/v) as an eluant to give 35 (65 mg, 80%). Oil;
1
IR (CH2Cl2) 3419, 2924, 1614 cm21; H NMR (CDCl3):
3.81 (s, 3H, OMe), 4.07 (s, 2H, Bn), 4.19 (bs, 2H, CH2OH),
4.46 (s, 2H, CH2OPMB), 5.14, 5.20 (2bs, 2H, vCH2),
6.88, 7.76 (2 m, 4H, Aryl); 13C NMR d 55.3, 64.8 (t),
71.6 (t), 72.0 (t), 113.5 (t), 113.9, 129.4, 130.0 (s), 145.1
(s), 159.3 (s); MS (EI-HR) m/z: (M)þ requires for
C12H16O3: 208.1099. Found: 208.1105; Anal. calcd for
C12H16O3 (208.25): C, 69.21; H, 7.74. Found: C, 69.63; H,
7.87.
1.3.1. (4S,6R) 4-Methyl-5-oxa-3-oxo-cepham (23). Mp
46–478C; [a]D¼þ35.6 (c 0.55, CH2Cl2); IR (CH2Cl2)
1777, 1738 cm21
;
1H NMR (CDCl3): 1.43 (d, 3H,
J¼6.7 Hz, Me), 2.94 (d, 1H, J¼15.3 Hz, H-7), 3.31 (ddd,
1H, J¼15.3, 3.4, 1.9 Hz, H-70), 3.70 (ddd, 1H, J¼19.2, 1.8,
0.7 Hz, H-2), 4.022 (bq, 1H, J¼6.7 Hz, H-4), 4.33 (d, 1H,
J¼19.2 Hz, H-2 ), 5.28 (dd, 1H, J¼3.4, 0.7 Hz, H-6); 13C
NMR d 15.4, 45.1 (t), 48.4 (t), 77.4, 78.7, 168.5 (s), 200.6
(s); Anal. calcd for C7H9NO3 (155.15): C, 54.19; H, 5.85; N,
9.03. Found: C, 54.20; H, 6.03; N, 9.05.
1.3.6. 2-Bromomethyl-3-(p-methoxybenzyloxy)-prop-1-
ene (36). The compound 36 was obtained from 35 (4 g,
19.2 mmol) according to the procedure described for
compound 21. The crude product was purified by chroma-
tography using hexane/t-BuOMe (95:5 v/v) as an eluant to
1
give 36 (4.4 g, 85%). Oil; IR (film) 2954, 1612 cm21; H
NMR (CDCl3): 3.81 (s, 3H, OMe), 4.04 (s, 2H, CH2Br),
4.12 (s, 2H, Bn), 4.47 (s, 2H, CH2OPMB), 5.25, 5.35 (bs,
1H, vCH2), 7.28, 6.89 (2 m, 4H, Aryl); 13C NMR d 33.1 (t),
55.3, 70.1 (t), 72.1 (t), 113.8, 117.2 (t), 129.4, 130.1 (s),
1.3.2. (4S,6S) 4-Methyl-5-oxa-3-oxo-cepham (24). Oil;
[a]D¼2269.2 (c 0.46, CH2Cl2); IR (CH2Cl2) 1776,
1748 cm21
;
1H NMR (CDCl3): 1.40 (d, 3H, J¼6.7 Hz,

Z. Kałuz˙a et al. / Tetrahedron 59 (2003) 5893–5903
5901
142.5 (s), 159.3 (s); MS (HR-EI) m/z: (M)þ requires for
C12H BrO2: 270.0255. Found: 270.0264; Anal. calcd for
C12H15BrO2 (271.15): C, 53.16; H, 5.58; Br, 29.47. Found:
C, 52.90; H, 5.68; Br, 29.34.
d 26.5, 30.9 (t), 55.3, 64.6 (t), 77.1 (s), 113.8, 118.6 (t),
128.9, 131.1 (s), 148.9 (s), 159.0 (s); MS (HR-LSIMS) m/z:
(MþNa)þ requires for C14H19O2Na79Br: 321.0466. Found:
321.0458; Anal. calcd for C14H19BrO2 (299.20): C, 56.20;
H, 6.40; Br, 26.71. Found: C, 56.22; H, 6.52; Br, 26.78.
79
15
1.3.7. 3-(p-Methoxybenzyloxy)-2,3-dimethyl-but-1-ene
(38). To the suspension of NaH (washed with hexane)
(216 mg, 9 mmol) in DMF (10 mL) the 2,3-dimethyl-but-1-
en-3-ol 3720 (600 mg, 6 mmol) was added dropwise. After
30 min, p-methoxy-benzyl chloride (780 mg, 680 mL,
5 mmol) was added. Subsequently, the reaction mixture
was stirred and heated to 408C until the p-methoxy-benzyl
chloride disappeared. The reaction mixture was poured into
cold water, extracted with hexane, dried and concentrated.
The crude product was purified by chromatography using
hexane/t-BuOMe (95:5 v/v) as an eluant to give 38 (490 mg,
1.3.11. (6) 1-[30-(p-Methoxybenzyloxy)-20-methylene-
propyl]-4-vinyloxy-azetidin-2-one (42). Compound 42
was obtained from 36 (59 mg, 0.22 mmol) and 4-vinyl-
oxy-azetidin-2-one (32 mg, 0.28 mmol) according to the
procedure described for 22. The crude product was purified
by chromatography using hexane/t-BuOMe (30:70 v/v) as
an eluant to give 42 (54 mg, 80%). Oil; IR (CH2Cl2)
1
1768 cm21; H NMR (CDCl3): 2.86 (d, 1H, J¼14.8 Hz,
H-3), 3.08 (dd, 1H, J¼14.8, 3.7 Hz, H-3), 3.72 (d, 1H,
J¼15.8 Hz, NCHH), 3.81 (s, 3H, OMe), 3.96 (s, 2H,
CH2OPMB), 4.04 (d, 2H, J¼15.8 Hz, NCHH), 4.16 (dd, 1H,
J¼6.7, 2.2 Hz, OCHvCHH), 4.33 (dd, 1H, J¼14.2, 2.2 Hz,
OCHvCHH), 4.43 (s, 2H, J¼10.7 Hz, Bn), 5.14, 5.24 (d,
2H, vCH2), 5.23 (bd, 1H, J¼3.7 Hz, C-4), 6.35 (dd, 1H,
J¼14.2, 6.7 Hz, OCHvCH2), 6.88, 7.26 (2 m, 4H, Aryl);
13C NMR d 43.3 (t), 44.8 (t), 55.3, 71.2 (t), 72.2 (t), 77.2,
80.2, 96.1 (t), 113.8, 116.0 (t), 129.5, 140.2 (s), 148.2 (s),
159.3 (s), 165.6 (s); MS (HR-LSIMS) m/z: (MþNa)þ
requires for C17H21NO4Na: 326.1368. Found: 326.1385;
Anal. calcd for C17H21NO4 (303.36): C, 67.31; H, 6.98; N,
4.62. Found: C, 67.07; H, 7.11; N, 4.48.
45%). Oil; IR (CH2Cl2) 2985, 1613 cm21 1H NMR
;
(CDCl3); 1.38 (s, 6H, 2Me), 1.80 (bs, 3H, Me), 3.78 (s,
3H, OMe), 4.19 (s, 2H, Bn), 4.97 (m, 2H, vCH2), 7.25, 6.85
(2 m, 4H, Aryl); 13C NMR d 18.5, 25.9, 55.3, 64.4 (t), 77.3
(s), 112.0 (t), 113.8, 128.9, 131.7 (s), 148.9 (s), 158.9 (s);
MS (HR-LSIMS) m/z: (MþNa)þ requires for C14H20O2Na:
243.1361. Found: 243.1350; Anal. calcd for C14H20O2
(220.31): C, 76.33; H, 9.15. Found: C, 76.48; H, 8.89.
1.3.8. 2-Chloromethyl-3-(p-methoxybenzyloxy)-3-
methyl-but-1-ene (39). The compound 39 was obtained
from 38 (2.3 g, 10.4 mmol) according to the procedure
described for compound 34. The crude product was purified
by chromatography using hexane/t-BuOMe (95:5 v/v) as an
eluant to give 39 (1.9 g, 72%). Oil; IR (CH2Cl2) 2984,
1.3.12. (6) 3-Methylene-5-oxa-cepham (43). To the stirred
solution of compound 42 (58 mg, 0.19 mmol) in CH2Cl2
(2 mL) at 08C, the BF3·Et2O (27 mg, 24 mL, 0.18 mmol)
was added. The mixture was stirred at 08C until dis-
appearance of the substrate (,0.5 h). Subsequently, the
saturated solution of NaHCO3 (3 mL) was added and
stirring was continued for 5 min. The mixture was poured
into cold water and extracted with ethyl acetate (3£). The
combined extracts were dried and concentrated. The crude
product was purified by chromatography using hexane/
t-BuOMe (25:75 v/v) as an eluant, followed by the
kugelrohr vacuum distillation (oven temp. 808C, 0.2 mm
1
1613 cm21; H NMR (CDCl3): 1.45 (s, 6H, 2Me), 3.80 (s,
3H, OMe), 4.19 (bs, 2H, CH2Cl), 4.21 (s, 2H, Bn), 5.39,
5.54 (2s, 2H, vCH2), 6.87, 7.24 (2 m, 4H, Aryl); 13C NMR
d 26.3, 43.4 (t), 55.3, 64.6 (t), 77.1 (s), 113.8, 116.4 (t),
128.9, 131.1 (s), 148.6 (s), 159.0 (s); MS (HR-LSIMS) m/z:
(MþNa)þ requires for C14H19O2Na35Cl: 277.0971. Found:
277.0970.
1.3.9. 2-Hydroxymethyl-3-(p-methoxybenzyloxy)-3-
methyl-but-1-ene (40). The compound 40 was obtained
from 39 (76 mg, 0.3 mmol) according to the procedure
described for compound 35. The crude product was purified
by chromatography using hexane/t-BuOMe (60:40 v/v) as
an eluant to give 40 (60 mg, 85%). Oil; IR (CH2Cl2) 3506,
Hg) to give 43 (13 mg, 50%). Oil; IR (CH2Cl2) 1767 cm21
;
1H NMR (CDCl3): 2.81 (d, 1H, J¼15.0 Hz, H-7), 3.17 (ddd,
1H, J¼15.0, 3.3, 1.9 Hz, H-70), 3.67 (bd, 1H, J¼15.4 Hz,
H-2), 4.20, 4.33 (2d, 2H, J¼13.0 Hz, H-4,40), 4.34 (d, 1H,
J¼15.4 Hz, H-20), 5.00, 5.05 (2 m, 2H, vCH2), 5.02 (d, 1H,
J¼3.3 Hz, H-6); 13C NMR d 43.4 (t), 45.3 (t), 69.8 (t), 77.3
(d), 113.2 (t), 135.3 (s), 167.3 (s); MS (LSIMS-HR) m/z:
(MþH)þ requires for C7H10NO2: 140.0712. Found:
140.0705; Anal. calcd for C7H9NO2 (139.15): C, 60.42;
H, 6.52; N, 10.07. Found: C, 59.90; H, 6.78; N, 9.68.
1
2984, 1614 cm21; H NMR (CDCl3): 1.45 (s, 6H, 2Me),
3.78 (s, 3H, OMe), 4.25 (bs, 2H, CH2OH), 4.28 (s, 2H, Bn),
5.17, 5.28 (2s, 2H, vCH2), 6.86, 7.23 (2 m, 4H, Aryl); 13
C
NMR d 26.1, 55.3, 63.5 (t), 64.4 (t), 77.5 (s), 111.7 (t),
113.9, 128.9, 131.1 (s), 151.7 (s), 159.0 (s); MS (HR-
LSIMS) m/z: (MþNa)þ requires for C14H20O3Na:
259.1310. Found: 259.1304; Anal. calcd for C14H20O3
(236.31): C, 71.16; H, 8.53. Found: C, 71.10; H, 8.60.
1.3.13. (6) 5-Oxa-3-oxo-cepham (44). The compound 44
was obtained from 43 (220 mg, 1.58 mmol) according to the
procedure described for 23 and 24. The crude product was
purified by chromatography using hexane/AcOEt (20:80
v/v) as an eluant to give 44 (190 mg, 85%). Oil; IR (CH2Cl2)
1.3.10. 2-Bromomethyl-3-(p-methoxybenzyloxy)-3-
methyl-but-1-ene (41). The compound 41 was obtained
from 40 (1.6 g, 6.6 mmol) according to the procedure
described for 21. The crude product was purified by
chromatography using hexane/t-BuOMe (95:5 v/v) as an
eluant to give 41 (1.8 g, 91%). Oil; IR (CH2Cl2) 2985,
1777, 1744 cm21
;
1H NMR (CDCl3): 2.99 (d, 1H,
J¼15.4 Hz, H-7), 3.32 (ddd, 1H, J¼15.4, 3.3, 1.8 Hz,
H-70), 3.74 (dt, 1H, J¼19.5, 1.8 Hz, H-2), 4.20, 4.38 (2bd,
2H, J¼17.4 Hz, H-4,40), 4.41 (d, 1H, J¼19.5 Hz, H-20), 5.26
(d, 1H, J¼3.3 Hz, H-6); 13C NMR d 44.6 (t), 48.9 (t), 71.8
(t), 77.2 (d), 168.7 (s), 199.3 (s); MS (EI-HR) m/z: Mþ
requires for C6H7NO3: 141.0426. Found:141.0419; Anal.
1
1614 cm21; H NMR (CDCl3): 1.47 (s, 6H, 2Me), 3.79 (s,
3H, OMe), 4.10 (bs, 2H, CH2Br), 4.20 (s, 2H, Bn), 5.43,
5.57 (2s, 2H, vCH2), 6.86, 7.23 (2 m, 4H, Aryl); 13C NMR

5902
Z. Kałuz˙a et al. / Tetrahedron 59 (2003) 5893–5903
calcd for C6H7NO3 (141.12): C, 51.06; H, 5.00; N, 9.92.
Found: C, 49.02; H, 5.27; N, 9.14.
(bd,0 1H, J¼15.1 Hz, H-3), 3.27 (dd, 1H, J¼15.1, 3.9 Hz,
H-3 ), 3.79 (s, 3H, OMe), 3.88 (d, 1H, J¼17.2 Hz, NCHH),
4.03 (bd, 1H, J¼17.2 Hz, NCHH), 4.19, 4.22 (2d, 2H,
J¼10.8 Hz, Bn), 5.11, 5.20 (2s, 2H, vCH2), 6.02 (dd, 1H,
J¼3.9, 1.2 Hz, C-4), 6.86, 7.26 (2m, 4H, Aryl); 13C NMR d
20.7, 25.9, 26.2, 41.6 (t), 44.8 (t), 55.3, 64.4 (t), 76.4, 76.5
(s), 111.8 (t), 113.8, 128.9, 131.1 (s), 147.1 (s), 158.9 (s),
165.6 (s), 170.5 (s); MS (HR-LSIMS) m/z: (MþH)þ
requires for C19H26O5N: 348.1811. Found: 348.1820;
Anal. calcd for C19H25NO5 (347.41): C, 65.69; H, 7.25;
N, 4.03. Found: C, 65.66; H, 7.17; N, 4.10.
1.3.14. (6) 1-[30-(p-Methoxybenzyloxy)-20-methylene-30-
methyl-butyl]-4-vinyloxy-azetidin-2-one (45). The com-
pound 45 was obtained from 41 (299 mg, 1.0 mmol) and
4-vinyloxy-azetidin-2-one (135 mg, 1.2 mmol) according to
the procedure described for 22. The crude product was
purified by chromatography using hexane/t-BuOMe (40:60
v/v) as an eluant to give 45 (230 mg, 70%). Oil; IR (CH2Cl2)
1
1768 cm21; H NMR (CDCl3): 1.43, 1.44 (2s, 6H, 2Me),
2.93 (d, 1H, J¼14.8 Hz, H-3), 3.16 (dd, 1H, J¼14.8, 3.6 Hz,
H-30), 3.82 (s, 3H, OMe), 3.88 (d, 1H, J¼17.0 Hz, NCHH),
4.12 (d, 1H, J¼17.0 Hz, NCHH), 4.17 (dd, 1H, J¼6.7,
2.2 Hz, OCHvCHH), 4.22, 4.25 (d, 2H, J¼10.7 Hz, Bn),
4.33 (dd, 1H, J¼14.3, 2.2 Hz, OCHvCHH), 5.18, 5.28 (s,
2H, vCH2), 5.30 (bd, 1H, J¼3.5 Hz, C–4), 6.35 (dd, 1H,
J¼14.3, 6.7 Hz, OCHvCH2), 6.88, 7.27 (2 m, 4H, Aryl);
13C NMR d 25.7, 26.0, 40.8 (t), 44.9 (t), 55.3, 64.5 (t), 76.5
(s), 80.1, 91.1 (t), 112.9 (t), 113.8, 129.0, 131.0 (s), 146.7
(s), 147.9, 159 (s), 165.8 (s); MS (HR-LSIMS) m/z:
(MþNa)þ requires for C19H25O4NaN: 354.1681. Found:
354.1695; Anal. calcd for C19H25NO4 (331.41): C, 68.86; H,
7.60; N, 4.23. Found: C, 68.75; H, 7.60; N, 4.16.
1.3.18. (6) 1-[20-Chloromethyl-30-methyl-but-20-enyl]-4-
acetoxy-azetidin-2-one (49). To the suspension of SnCl2
(57 mg, 0.3 mmol) in CH2Cl2 (1 mL), the TMS-Cl (130 mg,
152 mL, 1.2 mmol) was added. The mixture was stirred for
15 min and the solution of 48 (104 mg, 0.3 mmol) in
CH2Cl2 (0.5 mL) was added. Stirring was continued at room
temperature until disappearance of the substrate (,1 h). The
mixture was cooled to 08C and saturated solution of
NaHCO3 (2 mL) was added. The reaction mixture was
stirred for 5 min, poured into cold water and extracted with
CH2Cl2 (3£). The combined extracts were dried over
MgSO4 and concentrated. The crude product was purified
by chromatography using CH2Cl2: t-BuOMe (95:5 v/v) as
an eluant to give 49 (20 mg, 27%) and 46 (10 mg, 20%).
1.3.15. (6) 4,4-Dimethyl-3-methylene-5-oxa-cepham
(46). Compound 46 was obtained from 48 (230 mg,
0.66 mmol) according to the procedure described for 43
using BF3·Et2O (46 mg, 42 mL, 0.33 mmol). The reaction
mixture was quenched with saturated NaHCO3 after 1 h.
The crude product was purified by chromatography using
hexane/AcOEt (60:40 v/v) as an eluant to give 46 (55 mg,
Compound 49. Oil; IR (CH2Cl2) 1769, 1753 cm21; 1H NMR
(CDCl3): 1.82, 1.85 (2s, 6H, 2Me), 2.10 (s, 3H, Ac) 2.89
(bd,0 1H, J¼15.0 Hz, H-3), 3.25 (dd, 1H, J¼15.0, 3.9 Hz,
H-3 ), 3.88 (d, 1H, J¼15.0 Hz, NCHH), 4.05 (d, 1H,
J¼15.0 Hz, NCHH), 4.19, 4.15 (2d, 2H, J¼11.4 Hz,
CH2Cl), 5.99 (dd, 1H, J¼3.9, 1.2 Hz, H-4); 13C NMR d
20.8, 20.8, 41.1 (t), 43.6 (t), 44.9 (t), 76.1, 76.9, 123.6 (s),
139.7 (s), 165.5 (s), 170.4 (s); MS (LR-ESI) m/z: (MþNa)þ
requires for C11H16ClO3NNa: 245.1. Found: 245.1; Anal.
calcd for C11H16ClNO3 (245.70): C, 53.77; H, 6.56; N,
14.43; Cl, 14.43. Found: C, 56.80; H, 7.03; N, 5.46; Cl,
13.14.
50%). Oil; IR (CH2Cl2) 1766 cm21 1H NMR (CDCl3):
;
1.47, 1.52 (2s, 6H, 2Me), 2.79 (bd, 1H, J¼14.9 Hz, H-7),
3.19 (ddd, 1H, J¼14.9, 3.2, 1.7 Hz, H-70), 3.80 (bd, 1H,
J¼15.0 Hz, NCHH), 4.26 (d, 1H, J¼15.0 Hz, NCHH), 5.07,
4.95 (2 m, 2H, vCH2), 5.22 (d, 1H, J¼3.2 Hz, H-6); 13C
NMR d 23.7, 27.4, 42.6 (t), 45.9 (t), 72.9, 76.0 (s), 110.4 (t),
142.9 (s), 168.5 (s); MS (EI-HR) m/z: Mþ requires for
C9H13NO2: 167.0946. Found:167.0959.
1.3.16. (6) 4,4-Dimethyl-5-oxa-3-oxo-cepham (47). The
compound 47 was obtained from 46 (30 mg, 0.18 mmol)
according to the procedure described for 23 and 24. The
crude product was purified by chromatography using
hexane/AcOEt (60:40 v/v) as an eluant to give 47 (21 mg,
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2. Firestone, R. A.; Fahey, J. L.; Maciejewicz, N. S.; Patel, G. S.;
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