Transformation of the 7-isopropylidene group in 5-dethia-5-oxacephams

Article abstract of DOI:10.1016/S0040-4020(00)01098-X

[2+2]Cycloaddition of CSI to 5-O-protected-3-O-allenyl-1,2-O-isopropylidene-α-D-xylofuranoses 8 and 9 gave respective β-lactams 10-13 having an exo-propylidene group, in moderate stereoselectivity. Compounds 10, 11 and tetracyclic cephams 14, 15 obtained from 10 and 11 or 12 and 13, were used as substrates for a variety of transformations leading to the introduction of isopropyl, hydroxyisopropyl, oxygen and nitrogen functions, α to the β-lactam carbonyl group. These reactions proceeded in high stereoselectivity with control of the absolute configuration of the cephams formed.

Full text of DOI:10.1016/S0040-4020(00)01098-X

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1301±1309
Transformation of the 7-isopropylidene group in
5-dethia-5-oxacephams
p
Â
Robert èysek, Zo®a Urbanczyk-Lipkowska and Marek Chmielewski
Institute of Organic Chemistry of the Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Received 6 July 2000; revised 30 October 2000; accepted 16 November 2000
AbstractÐ[212]Cycloaddition of CSI to 5-O-protected-3-O-allenyl-1,2-O-isopropylidene-a-d-xylofuranoses 8 and 9 gave respective
b-lactams 10±13 having an exo-propylidene group, in moderate stereoselectivity. Compounds 10, 11 and tetracyclic cephams 14, 15
obtained from 10 and 11 or 12 and 13, were used as substrates for a variety of transformations leading to the introduction of isopropyl,
hydroxyisopropyl, oxygen and nitrogen functions, a to the b-lactam carbonyl group. These reactions proceeded in high stereoselectivity
with control of the absolute con®guration of the cephams formed. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
is one of the most common methods of the b-lactam ring
formation. Regiospeci®c formation of the azetidin-2-one
ring by this method requires an activation of the double
bond of the ole®n by an electron-donating substituent at
one terminal only.2 This signi®cantly reduces the possibility
of a direct functionalization of the azetidin-2-one ring by
suitable preparation of the starting ole®n.
Studies on b-lactam antibiotics have shown that the carbon
atom next to the carbonyl group, that is C-6 of penams and
C-7 of cephams, can be substituted by a variety of groups
without loss of high biological activity.1 The [212]cyclo-
addition of chlorosulfonyl isocyanate to nucleophilic ole®ns
Chart 1.
Keywords: cephams; carbohydrates; stereocontrol.
Corresponding author. Tel.: 148-22-632-3789; fax: 148-22-632-6681; e-mail: chmiel@icho.edu.pl
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01098-X

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R. èysek et al. / Tetrahedron 57 (2001) 1301±1309
Chart 2.
Scheme 1.
Buynak and coworkers3±8 have introduced an attractive
entry to 3-alkylidene azetidin-2-ones, based on [212]-
cycloaddition of CSI to allenyl derivatives. The value of
this strategy is that the exo-double bond not only exists in
a number of antibiotics and b-lactamase inhibitors such as
asparenomycins 1,9 alkylidenepenicillins 2,10 3,11 and alkyl-
idenecephalosporins 412 (Chart 1), but also that it can be
transformed into isopropyl,3 hydroxyisopropyl 5,8 bromo-
6,3 hydroxy- 6,3 and oxo-isopropylidene 73 residues (Chart
2).
It was of interest to explore application of Buynak's
Scheme 2.

R. èysek et al. / Tetrahedron 57 (2001) 1301±1309
1303
Chart 3.
The present paper reports on the transformation of the exo-
double bond into alkyl, keto, hydroxy, and amino functions
with control of the con®guration at the C-7 stereogenic
center of the cepham skeleton.
Scheme 3.
2. Results and discussion
methodology3±8 to 7-substituted-5-oxacephams and to
demonstrate that the isopropylidene substituent can be
used to introduce oxygen and nitrogen functionality at the
C-7 carbon atom.
The sodium in liquid ammonia reduction of the epimeric 10/
11 mixture led to corresponding trans substituted azetidin-
2-ones 16 and 17. Compounds 16 and 17 were separated
and, independently, subjected to intramolecular alkylation
under the standard reaction sequence14 to afford cephams 20
and 21, respectively (Scheme 2). The con®guration of both
compounds was assigned by 1H NMR. The coupling
constant J3 ,4 below resolution (i.e. ,1 Hz) testi®ed to the
trans substitution of the four-membered ring in both
compounds. NOEs, measured for compound 21, showed a
spin±spin interaction between H-3 (d 4.15 ppm) and H-40
(d 4.62 ppm) protons. Irradiation of the H-3 signal caused
enhancement of the H-40 signal by 6.0% and conversely, the
signal due to H-3 was enhanced by 6.0% when H-40 was
irradiated. Compound 20 has the same isopropyl substituent
a to the b-lactam carbonyl group and the con®guration
around the four-membered ring to that of PS-6 antibiotic
2215 (Chart 3). Further transformations were performed on
cephams 14 and 15, obtained and separated into pure
epimers by the procedure described previously.13
Recently, we have reported on stereoselective [212]-
cycloadditions of CSI to the alkoxyallenes 8 and 9 derived
from 1,2-O-isopropylidene-a-d-xylofuranose.13 Cyclo-
adducts 10, 11 and 12, 13, thus obtained, were deprotected
at C-5 of the sugar to give respective mixtures of the same
diastereomers. Subsequent tosylation and the intramolecular
alkylation of the b-lactam nitrogen atom afforded
compounds 14 and 15 having the 5-oxacepham skeleton
with the 7-exo-double bond suitable for further transfor-
mations (Scheme 1). (For the sake of simplicity, in number-
ing of tetracyclic cephams the reader is referred to combine
sugar and azetidinone nomenclature.) It should be pointed
out that, in comparison with Buynak's3±8 compounds,
introduction of an oxygen funcion to the C-4 of the azetidin-
2-one ring makes our 5-oxacephams more sensitive to the
b-elimination reaction.
0
0
Scheme 4.

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R. èysek et al. / Tetrahedron 57 (2001) 1301±1309
Figure 1. Molecular structure of the compound 29 with the crystallographic numbering scheme.
Hydrogenation of the double bond in 14 led to compound 24
having cis hydrogen atoms at C(30) and C(40), the alterna-
tive con®guration to that afforded by the Na/NH3 reduction
of the double bond in 10 and 11 (Scheme 3).
In order to cleave the double bond in 14 and 15 a two-step
reaction sequence was applied. Oxidation of the cepham 14
with RuCl3/NaIO4 in H2O/CH3CN/CCl4 mixture20 in the
presence of CaCO3, for 5 min, afforded diol 29 in 85%
yield (Scheme 4). The structure and con®guration of 29
was demonstrated by X-ray crystallography (Fig. 1, cf.
Experimental).
Treatment of 14 with NBS in wet DMSO,16 according to the
procedure of Buynak and Rao,8 provided bromohydrins 25
and 26 in the ratio of about 3.8:1, respectively. The con-
®guration of 25 and 26 was assigned by the assumption that
Br1 would approach the double bond for the least hindered
side. Tributyltin hydride reduction of the mixture 25/26
yielded a mixture of a-hydroxyisopropyl b-lactams 27
and 28 in the ratio of ca. 6.5:1 (Scheme 4). A relatively
high stereoselectivity of debromination followed from
previous observations.8,17 Tin hydride attacks the radical,
obtained from both bromohydrins (25/26), anti to the
C(40) oxygen atom to produce the predominantly cis
disubstituted compound 27. The major product was easily
isolated from the post-reaction mixture by crystallization
from ethyl acetate/hexane solution. This two-step reaction
sequence led to the construction of the side chain of
carpetimycin A 23.18
cis-Hydroxylation of the cepham 15, under the same con-
ditions,20 gave a mixture of diols 30 and 31 in a ratio of ca.
6.4:1, respectively. Con®guration of the major product 30
was tentatively assigned by an assumption that RuO4
approaches preferentially the double bond anti to the
oxygen atom at C-40 of the azetidin-20-one ring (Scheme 5).
Glycolic cleavage of the diol 29 using the standard con-
ditions (NaIO4 in H2O/THF or Bu4NIO4 in boiling
CH2Cl2) failed to give a-keto b-lactam due to the slow
oxidation process. Application of Pb(OAc)4 in CH2Cl2
was also unsuccessful, causing decomposition of the
substrate. The cleavage, providing 32 was performed
using H6IO5 in AcOEt.21 Owing to its stability, compound
32 was used for further steps without puri®cation. It should
be pointed out that a-keto b-lactams are known to be very
useful intermediates owing to the chemically very active22
keto function. Reduction of 32 with NaBH4 in methanol
gave the alcohol 33 having cis oxygen atoms at the
b-lactam ring (Scheme 6). We failed to transform the
ketone 32 into the corresponding oxime due to decompo-
sition of the substrate under the standard reaction conditions.
Ozonolysis of the double bond in both compounds 14 and 15
(2658C, CH2Cl2 or AcOEt) led to the formation of polar
products which were not investigated further since they did
not show any carbonyl absorptions in IR spectra. Decom-
position of the azetidin-2-one ring during the ozonolysis
of a-ethylidene-azetidin-2-ones has been reported pre-
viously.19
Scheme 5.

R. èysek et al. / Tetrahedron 57 (2001) 1301±1309
1305
Scheme 6.
Glycolic cleavage of the mixture 30 and 31, under the con-
ditions used for 29, afforded an unstable mixture of the
a-keto b-lactam 35 and the hydrate 36. The crude mixture
of 35/36 was reduced with NaBH4 to the alcohol 37
(Scheme 7). The mixture 35/36 treated with NH2OH´HCl
in pyridyne to yield a mixture of oximes 39, which reduced
with hydrogen over PtO2 in the presence of Ac2O/AcONa,
to give the N-acetyl compound 40 in 65% yield (Scheme 7).
functionalization of the unsubstituted CH2 group,23 particu-
larly that the latter usually proceeds via a carbanion stage
which may cause a b-elimination of the 4-alkoxy fragment.
3. Experimental
3.1. General
In summary, we have demonstrated that the [212]cyclo-
adducts of CSI to 3-O-allenyl-a-d-xylofuranoses 10/11
are versatile intermediates for the preparation of a wide
range of 7-substituted-5-oxacephams. Recently, we have
shown that the tetracyclic oxacepham skeleton can be
transformed into a bicyclic 5-oxacephem system.24 Except
the cycloaddition reaction that proceeds with a moderate
stereoselectivity,13 the other reactions offer high stereo-
selectivities and may provide substituents at C-7 existing
in many active b-lactam antibiotics. Functionalization of
the 4-alkoxyazetidin-2-one ring via the 3-isopropylidene
residue offers certain advantages over the corresponding
Melting points were determined on a Ko¯er hot-stage
apparatus with microscope. 1H NMR spectra were obtained
on Brucker Avance 500 and Varian Gemini AC-200
spectrometers for solution in acetone-d6 or CDCl3 with
tetramethylsilane as an internal standard and are expressed
as d values. IR spectra were recorded on a Perkin±Elmer
FT-IR Spectrum 2000 spectrophotometer. Mass spectra
were determined with an AMD 604 Inectra GmbH spectro-
meter. Optical rotations were measured using a JASCO P
3010 polarimeter at ambient temperature. Column chroma-
tography was performed on Merck silica gel (230±400
Scheme 7.

1306
R. èysek et al. / Tetrahedron 57 (2001) 1301±1309
mesh). All solvents were dried and puri®ed by standard
techniques.
3.1.4. (30S,40S) 3-O-(30-Isopropyl-azetidin-20-on-40-yl)-
1,2-O-isopropylidene-5-O-tosyl-a-d-xylofuranose (19).
Compound 19 was obtained from 17 by the tosylation
procedure (tosyl chloride, pyridine, 12 h; 78%). Oil;
[Found: C, 55.46; H, 6.70; N, 2.98. C21H29O8NS (455.54)
3.1.1. (40R) and (40S) 1,2-O-Isopropylidene-3-O-[30-(1-
methylethylidene)-azetidin-20-on-40-yl]-5-O-trityl-a-d-
xylofuranose (10 and 11). The mixture of stereoisomers
10/11 was obtained according to the known procedure
(60%).13
22
requires C, 55.37; H, 6.42; N, 3.07%]; ‰aŠ ˆ229.2 (c 0.21,
D
CH2Cl2); nmax (®lm) 3327, 1770 cm21; dH (500 MHz,
CDCl3) 7.31±7.85 (2m, 4H, tosyl), 6.43 (br s, 1H, NH),
5.86 (d, 1H, J 3.5, Hz, H-1), 4.89 (d, 1H, J 1.0 Hz, H-40),
4.48 (d, 1H, J3.5 Hz, H-2), 4.39 (ddd, 1H, J 3.0, 5.0, 8.0 Hz,
H-4), 4.24 (dd, 1H, J 8.0, 9.5 Hz, H-5b), 4.11 (dd, 1H, J 5.0,
9.5 Hz, H-5a), 4.04 (d, 1H, J3.0 Hz, H-3), 2.79 (dd, 1H, J
1.0, 8.0 Hz, H-30), 2.46 (s, 3H, tosyl), 1.95±2.05 (m, 1H,
ZCHMe2), 1.31, 1.46 (2s, 6H, isoprop.), 1.08 (d, 3H, J
6.5 Hz, Me), 1.03 (d, 3H, J 6.5 Hz, Me); HRMS
(EI) m/z: M1 found 455.1608. C21H29O8NS requires
455.1614.
3.1.2. (30R,40R) and (30S,40S) 3-O-(30-Isopropyl-azetidin-
20-on-40-yl)-1,2-O-isopropylidene-a-d-xylofuranose (16
and 17). To a solution of sodium (0.21 g, 9.23 mmol) in
liquid ammonia (40 mL) the mixture of 10/11 (0.5 g,
0.92 mmol) in dry THF (2 mL) was added dropwise. The
mixture was stirred at 2608C for 25 min. Subsequently,
ammonium chloride (0.5 g) was added and ammonia was
allowed to evaporate. The post-reaction mixture was treated
with water (10 mL) and extracted with AcOEt (3£15 mL).
The residue was separated by column chromatography on
silica gel, using hexane/ethyl acetate 3.5:6.5 v/v as an
eluent, to give the title compounds 16 (0.134 g, 48%) and
17 (0.067 g, 24%).
3.1.5. (30R,40R) 5-Deoxy-3-O:5-C-(30-isopropyl-azetidin-
20-on-10,40-di-yl)-1,2-O-isopropyli-dene-a-d-xylofura-
nose (20). Compound 20 was obtained from 18 according to
the procedure described for 14/1513 (86%). Colorless
crystals; mp 106±109.58C; [Found: C, 59.70; H, 7.74; N,
4.73. C14H21O5N (283.33) requires C, 59.35; H, 7.47; N,
22
D
16: Oil; ‰aŠ ˆ25.3 (c 0.25, CH2Cl2); nmax (CH2Cl2) 3606,
3398, 1774 cm21; dH (200 MHz, CDCl3) 6.55 (br s, 1H,
NH), 5.95 (d, 1H, J 4.0 Hz, H-1), 4.96 (d, 1H, J 1.5 Hz,
H-40), 4.56 (d, 1H, J4.0 Hz, H-2), 4.31±4.35 (m, 1H,
H-4), 4.06 (d, 1H, J 3.5 Hz, H-3), 3.74±3.78 (1m, 1H,
H-5a), 3.89±3.93 (m, 1H, H-5b), 2.89 (dd, 1H, J 1.5,
8.5 Hz, H-30), 1.90±2.10 (m, 1H, ZCHMe2), 1.33, 1.50
(2s, 6H, isoprop.), 1.09 (d, 3H, J 6.5 Hz, Me), 1.03 (d, 3H,
J 6.5 Hz, Me); HRMS (EI) m/z: (MZCH3)1 found: 286.
1275. C13H20O6N requires 286.1291.
4.94%]; ‰aŠ ˆ1118.6 (0.31, CH2Cl2); nmax (CH2Cl2)
22
D
1762 cm21; dH (500 MHz, CDCl3) 5.97 (d, 1H, J 3.5 Hz,
H-1), 4.73 (s, 1H, H-40), 4.61 (d, 1H, J 3.5 Hz, H-2), 4.40±
4.42 (m, 1H, H-4), 4.29 (d, 1H, J 3.0 Hz, H-3), 3.80 (dd, 1H,
J 4.5, 14.0 Hz, H-5b), 3.51 (dd, 1H, J 1.5, 14.0 Hz, H-5a),
2.78 (d, 1H, J 8.0 Hz, H-30), 1.33, 1.49 (2s, 6H, isoprop.),
1.96±2.03 (m, 1H, ZCHMe2), 1.05 (d, 3H, J 6.5 Hz, Me),
0.95 (d, 3H, J 6.5 Hz, Me); HRMS (EI) m/z: M1 found
283.1442. C14H21O5N requires 283.1420.
22
17: Oil; ‰aŠ ˆ229.2 (c 0.35, CH2Cl2); nmax (®lm) 3605,
3.1.6. (30S,40S) 5-Deoxy-3-O:5-C-(30-isopropyl-azetidin-
20-on-10,40-di-yl)-1,2-O-isopropylidene-a-d-xylofura-
nose (21). Compound 21 was obtained from 19 according to
the procedure described for 14/1513 (80%). Colorless
crystals; mp 99±1058C; [Found: C, 59.51; H, 7.62; N,
4.91. C14H21O5N (283.33) requires C, 59.35; H, 7.47; N,
D
3399, 1773 cm21; dH (500 MHz, CDCl3) 6.70 (br s, 1H,
NH), 5.95 (d, 1H, J 3.5 Hz, H-1), 4.84 (d, 1H, J 0.5 Hz,
H-40), 4.44 (d, 1H, J3.5 Hz, H-2), 4.19-4.23 (m, 1H, H-4),
3.9 (d, 1H, J 3.0 Hz, H-3), 3.83 (dd, 1H, J 4.5, 10.5 Hz,
H-5b), 3.71 (dd, 1H, J 5.5, 10.5 Hz, H-5a), 2.81 (d, 1H, J
8.0 Hz, H-30), 2.02 (br s, 1H, ZOH), 1.89±1.96 (m, 1H,
ZCHMe2), 1.24, 1.42 (2s, 6H, isoprop.), 0.99 (d, 3H, J
6.5 Hz, Me), 0.95 (d, 3H, J 6.5 Hz, Me); HRMS (LSIMS)
m/z: (M1Na)1 found 324.1407. C14H23O6NNa requires
324.1423.
22
4.94%]; ‰aŠ ˆ225.5 (c 0.18, CH2Cl2); nmax (®lm)
D
1754 cm21; dH (500 MHz, CDCl3) 5.88 (d, 1H, J 3.5 Hz,
H-1), 4.62 (s, 1H, H-40), 4.49 (d, 1H, J 3.5 Hz, H-2), 4.08 (d,
1H, J 15.0 Hz, H-5b), 4.03±4.05 (m, 1H, H-4), 3.23 (dd, 1H,
J 4.0, 15.0 Hz, H-5a), 2.84 (d, 1H, J 8.0 Hz, H-30), 1.96±
2.03 (m, 1H, ZCHMe2), 1.31, 1.49 (2s, 6H, isoprop.), 1.06
(d, 3H, J 6.5 Hz, Me), 1.00 (d, 3H, J 6.5 Hz, Me); HRMS
(EI) m/z: M1 found 283.1438. C14H21O5N requires
283.1420.
3.1.3. (30R,40R) 3-O-(30-Isopropyl-azetidin-20-on-40-yl)-
1,2-O-isopropylidene-5-O-tosyl-a-d-xylofuranose (18).
Compound 18 was obtained from 16 by the tosylation
procedure (tosyl chloride, pyridine, 12 h; 85%). Colorless
crystals; mp 131±1338C; [Found: C, 55.54; H, 6.67; N, 2.81.
C21H29O8NS (455.54) requires C, 55.37; H, 6.42; N, 3.07%];
3.1.7. (30S,40R) 5-Deoxy-3-O:5-C-(30-isopropyl-azetidin-
20-on-10,40-di-yl)-1,2-O-isopropyli-dene-a-d-xylofura-
nose (24). The mixture of 14 (0.03 g, 0.11 mmol) and PtO2
(0.015 g) in MeOH (10 mL) was shaken on a Parr hydro-
genator at 30 psi for 10 h. The solution was then concen-
trated and puri®ed by ¯ash chromatography (30% ethyl
acetate/hexane) to yield 0.019 g (63%) of the title
22
D
‰aŠ ˆ217.9 (c 1.08, CH2Cl2); nmax (CH2Cl2) 3397,
1776 cm21; dH (500 MHz, CDCl3) 7.31±7.85 (2m, 4H,
tosyl), 6.33 (br s, 1H, NH), 5.87 (d, 1H, J 3.5 Hz, H-1),
4.97 (d, 1H, J 1.0 Hz, H-40), 4.51 (d, 1H, J3.5 Hz, H-2),
4.37 (ddd, 1H, J 3.5, 5.0, 8.0 Hz, H-4), 4.24 (dd, 1H, J
8.0, 9.5 Hz, H-5b), 4.11 (dd, 1H, J 5.0, 9.5 Hz, H-5a),
4.08 (d, 1H, J3.5 Hz, H-3), 2.85 (dd, 1H, J 1.0, 9.0 Hz,
H-30), 2.46 (s, 3H, tosyl), 1.94±2.04 (m, 1H, ZCHMe2),
1.30, 1.46 (2s, 6H, isoprop.), 1.08 (d, 3H, J 6.5 Hz, Me),
1.02 (d, 3H, J 6.5 Hz, Me); HRMS (EI) m/z: M1 found
455.1583. C21H29O8NS requires 455.1614.
22
D
compound 24 as an oil; ‰aŠ ˆ159.6 (0.53, CH2Cl2); nmax
(®lm) 1757 cm21; dH (500 MHz, CDCl3) 5.97 (d, 1H, J
4.0 Hz, H-1), 4.98 (d, 1H, J 3.5 Hz, H-40), 4.62 (d, 1H, J
4.0 Hz, H-2), 4.43 (ddd, 1H, J 1.5, 3.0, 4.5 Hz, H-4), 4.30 (d,
1H, J 3.0 Hz, H-3), 3.80 (dd, 1H, J 4.5, 14.0 Hz, H-5b), 3.51
(dt, 1H, J 1.5, 14.0 Hz, H-5a), 2.88 (ddd, 1H, J 1.5, 3.5,

R. èysek et al. / Tetrahedron 57 (2001) 1301±1309
1307
11.5 Hz, H-30), 2.08±2.16 (m, 1H, ZCHMe2), 1.33, 1.49
(2s, 6H, isoprop.), 1.12 (d, 3H, J 6.5 Hz, Me), 0.93 (d, 3H,
J 6.5 Hz, Me); HRMS (EI) m/z: M1 found 283.1424.
C14H21O5N requires 283.1420.
3.1.10. (30R,40R) 5-Deoxy-3-O:5-C-[30-hydroxy-30-(1-hy-
droxy-1-methyl-ethyl)-azetidin-20-on-10,40-di-yl]-1,2-O-
isopropylidene-a-d-xylofuranose (29). Into a well-stirred
mixture of H2O (7.5 mL), CH3CN (5 mL) and CCl4 (5 mL)
were added NaIO4 (0.375 g, 1.76 mmol), CaCO3 (0.07 g,
0.70 mmol) and RuCl3´xH2O (0.003 g, 0.015 mmol). The
resulting mixture was cooled to 08C and the solution of 14
(0.1 g, 0.355 mol) in CCl4 (0.5 mL) was added dropwise.
Stirring was continued at 08C for 5 min; subsequently the
reaction was quenched by the addition of i-propanol (1 mL).
The precipitate was ®ltered on Celite and washed with ethyl
acetate (2£10 mL). The combined ®ltrates were dried
(MgSO4) and the solvent was evaporated. Puri®cation on
silica gel, using hexane/ethyl acetate 4:6 v/v as an eluent
gave the title compound 29 (0.1 g, 85%). Colorless crystals;
mp 198±2038C; [Found: C, 53.29; H, 6.78; N, 4.48.
C14H21O7N (315.33) requires C, 53.33; H, 6.71; N,
3.1.8. (30R,40R) and (30S,40R) 5-Deoxy-1,2-O-isopropyl-
idene-3-O:5-C-[30-bromo-30-(1-hydroxy-1-methyl-ethyl)-
azetidin-20-on-10,40-di-yl)-a-d-xylofuranose (25 and 26).
N-Bromosuccinimide (0.095 g, 0.53 mmol) was added to a
solution of 14 (0.1 g, 0.35 mmol) and H2O (0.26 mL,
1.42 mmol) in DMSO (1.5 mL). The resulting solution
was stirred at room temperature for 6 h and then poured
into a two-phase system water/ether. The aqueous phase
was extracted with ether, and the combined ether layers
were washed with brine, dried (MgSO4) and concentrated.
Puri®cation by ¯ash chromatography (30% ethyl acetate/
hexane) yielded 0.074 g (57%) of bromohydrins 25 and 26
in a ratio ca. 3.8:1, respectively. [Found: C, 44.60; H, 5.58;
N, 3.76. C14H20O6NBr (378.23) requires C, 44.46; H, 5.33;
N, 3.70%]; nmax (CH2Cl2) 3476, 1779 cm21; 25 (major
isomer): dH (500 MHz, CDCl3) selective signals taken
from the spectrum of the mixture: d 4.67 (d, 1H, J4.0 Hz,
H-2), 5.13 (s, 1H, H-40), 5.98 (d, 1H, J4.0 Hz, H-1).
22
4.44%]; ‰aŠ ˆ1126.7 (0.4, CH2Cl2); nmax (®lm) 3407,
D
3281, 1760 cm21; dH (200 MHz, CDCl31D2O) 5.98 (d,
1H, J 3.5 Hz, H-1), 4.96 (s, 1H, H-40), 4.66 (d, 1H, J
3.5 Hz, H-2), 4.43±4.48 (m, 1H, H-4), 4.40 (d, 1H, J
3.0 Hz, H-3), 3.75 (d, 2H, J 3.0 Hz, H-5a, H-5b), 1.41 (s,
3H, Me), 1.34 (s, 3H, Me), 1.33, 1.50 (2s, 6H, isoprop.);
HRMS (EI) m/z: (MZCH3)1 found 300.1073. C13H18O7N
requires 300.1083.
26 (minor isomer): dH (500 MHz, CDCl3) selective signals
taken from the spectrum of the mixture: 6.01 (d, 1H,
J4.0 Hz, H-1), 5.29 (s, 1H, H-40), 4.68 (d, 1H, J4.0 Hz,
H-2); HRMS (EI) m/z: (MZCH3)1 found 362.0257.
C13H17O6NBr requires 362.0239.
3.1.11. X-Ray structure determination of compound 29.
Single crystals of 29 suitable for X-ray structure analysis
were obtained by a slow evaporation of the i-propanol solu-
tion. Unit cell dimensions were obtained by least-squares ®t
of setting angles of 25 re¯ections collected in the u range
18.97±43.088. Data were collected on the Nonius BV
MACH 3 diffractometer with graphite monochromatized
CuKa radiation. Intensities were corrected for Lorentz
polarization and c-scan-based absorption factors (min. and
max. transmission 87.4 and 99.3%, respectively). Structures
were solved by direct methods with the use of SHELX8625
and re®ned against F2 using SHELX9726 programs. All
hydroxyl H-atoms were placed in ideal positions and re®ned
with the riding model and ®xed isotropic displacement para-
meters. Position for hydroxyl hydrogens were found from
different Fourier maps and re®ned without constraints.
Crystal data, details of data collection and re®nement pro-
cedure are deposited at the Cambridge Crystallographic
Data Center. (Crystallographic data have been deposited
at the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
and copies can be obtained on request, free of charge, by
quoting the publication citation and the deposition number
CCDC #151371.) The molecular structure of 29 is shown in
Fig. 1.
3.1.9. (30S,40R) and (30R,40R) 5-Deoxy-3-O:5-C-[30-(1-
hydroxy-1-methyl-ethyl)-azetidin-20-on-10,40-di-yl]-1,2-
O-isopropylidene-a-d-xylofuranose (27 and 28). A
solution of tributyltin hydride (0.85 mL, 0.317 mmol) and
AIBN (0.0065 g, 0.04 mmol) in toluene (1 mL) was added
to a hot (1008C) solution of bromohydrins 25/26 (0.06 g,
0.16 mmol) in toluene (3 mL). The reaction was allowed
to stir at this temperature for 20 min, then the solvent was
removed, and the product was puri®ed by ¯ash chroma-
tography, using CH2Cl2/ethyl acetate/hexane 1:5:4 v/v as
an eluent, to give the title compounds 27/28 in a ratio ca.
6.5:1 (0.043 g, 91%); nmax (CHCl3) 3509, 1755 cm21; 28:
dH (500 MHz, CDCl3) selective signals taken from the
spectrum of the mixture 27/28: 4.92 (d, 1H, J 0.5 Hz,
H-40), 4.63 (d, 1H, J 4.0 Hz, H-2), 4.30 (d, 1H, J 3.0 Hz,
H-3), 3.82 (dd, 1H, J4.5 and 14.0 Hz, H-5b), 3.56 (dd, 1H, J
2.0 and 14.0 Hz, H-5a), 3.01 (br s, 1H, ZOH); HRMS (EI)
m/z: (MZCH3)1 found 284.1141. C13H18O6N requires
284.1134.
After crystallization from AcOEt/hexane mixture, pure
compound 27 was obtained. Colorless crystals; mp 146.5±
1528C; [Found: C, 55.96; H, 7.22; N, 4.57. C14H21O6N
3.1.12. (40R) 3-O:5-C-[Azetidin-20,30-dion-10,40-di-yl)-5-
deoxy-1,2-O-isopropylidene-a-d-xylo-furanose (32). To
the solution of the diol 29 (0.053 g, 0.17 mmol) in dry
ethyl acetate (5 mL) H6IO5 (0.043 g, 0.192 mmol) was
added, and the mixture was stirred under argon for ,2.5 h
(TLC) at room temperature. The precipitate was ®ltered off,
washed with AcOEt (2£5 mL) and the combined ®ltrates
were concentrated in vacuo to give the crude a-keto
b-lactam 32 (0.062 g); nmax (CH2Cl2): 3343, 1782,
1761cm21; dH (500 MHz, acetone-d6) 6.13 (d, 1H, J
4.0 Hz, H-1), 5.50 (s, 1H, H-40), 4.79 (d, 1H, J 4.0 Hz,
H-2), 4.70±4.71 (m, 1H, H-4), 4.48 (d, 1H, J 3.0 Hz,
22
(299.33) requires C, 56.18; H, 7.07; N, 4.68%]; ‰aŠ ˆ
D
166.8 (0.63, CH2Cl2); nmax (CH2Cl2) 3543, 1768 cm21
;
dH (500 MHz, CDCl3) 5.98 (d, 1H, J 4.0 Hz, H-1), 5.12
(d, 1H, J 3.5 Hz, H-40), 4.67 (d, 1H, J 4.0 Hz, H-2), 4.45±
4.47 (m, 1H, H-4), 4.42 (d, 1H, J 3.0 Hz, H-3), 3.80 (dd, 1H,
J4.0, 13.5 Hz, H-5b), 3.59 (br d, 1H, J 13.5 Hz, H-5a), 3.24±
3.26 (m, 1H, H-30), 2.95 (br s, 1H, ZOH), 1.41 (s, 3H, Me),
1.34 (s, 3H, Me), 1.33, 1.50 (2s, 6H, isoprop.); HRMS (EI)
m/z: (MZCH3)1 found 284.1126. C13H18O6N requires
284.1134.

1308
R. èysek et al. / Tetrahedron 57 (2001) 1301±1309
H-3), 3.99 (dd, 1H, J 4.0, 13.5 Hz, H-5b), 3.79 (dd, 1H, J
2.0, 13.5 Hz, H-5a), 1.30, 1.42 (2s, 6H, isoprop.).
stability, the crude mixture 35/36 was used for the next
steps.
3.1.13. (30S,40R) 5-Deoxy-3-O:5-C-[30-hydroxy-azetidin-
20-on-10,40-di-yl]-1,2-O-isopropylidene-a-d-xylofuranose
(33). To the solution of the crude compound 32 (0.05 g) in
MeOH (4 mL), NaBH4 (0.0075 g, 0.2 mmol) was added.
After being stirred for 25 min at room temperature, AcOH
(0.05 mL) was added to the reaction mixture. The mixture
was evaporated and puri®ed by column chromatography on
silica gel (50% ethyl acetate/hexane) to give the title
compound 33 (0.027 g), which was characterized as the
3.1.16. (30R,40S) 5-Deoxy-3-O:5-C-[30-hydroxy-azetidin-
20-on-40-yl]-1,2-O-isopropylidene-a-d-xylofuranose (37).
Compound 37 was obtained from 35/36 according to the
procedure described for 33 (65%). Colorless crystals; mp
22
229±2328C; ‰aŠ ˆ19.3 (0.12, MeOH); nmax (KBr) 3428,
D
1751 cm21; dH (500 MHz, acetone-d61D2O) 5.92 (d, 1H, J
3.5 Hz, H-1), 4.99 (d, 1H, J 3.0 Hz, H-40), 4.78±4.80 (m,
1H, H-30), 4.56 (d, 1H, J 3.5 Hz, H-2), 4.29±4.31 (m, 1H,
H-3), 4.04±4.06 (m, 1H, H-4), 3.85 (d, 1H, J15.0 Hz, H-5b),
3.39 (ddd, 1H, J 1.5, 3.5, 15.0 Hz, H-5a), 1.28, 1.42 (2s, 6H,
isoprop.); HRMS (EI) m/z: (MZCH3)1 found 242.0687.
C11H15O6N requires 242.0664.
22
30-acetate 34. Oil; ‰aŠ ˆ1117.3 (0.4, CH2Cl2); nmax
D
(CHCl3): 1783, 1756 cm21; dH (500 MHz, acetone-d6)
6.03 (d, 1H, J 4.0 Hz, H-1), 5.56 (dd, 1H, J 1.5, 3.0 Hz,
H-30), 5.15 (d, 1H, J 3.0 Hz, H-40), 4.62 (d, 1H, J 4.0 Hz,
H-2), 4.31 (ddd, 1H, J 1.5, 3.0, 5.0 Hz, H-4), 4.32 (dd, 1H, J
0.5, 3.0 Hz, H-3), 3.90 (dd, 1H, J 4.5, 14.0 Hz, H-5b), 3.39
(dt, 1H, J 1.5, 14.0 Hz, H-5a), 2.11 (s, 3H, Ac), 1.30, 1.43
(2s, 6H, isoprop); HRMS (EI) m/z: (MZCH3)1 found
284.0757. C12H14O7N requires 284.07703.
3.1.17. (30R,40S) 3-O:5-C-[30-Acetoxy-azetidin-20-on-40-
yl]-5-deoxy-1,2-O-isopropylidene-a-d-xylofuranose (38).
Acetylation of 37 (acetic anhydride/pyridine mixture, 2:1
v/v; 1 h), gave the title compound 38 (88%). Colorless
22
D
crystals; mp 227±2298C; ‰aŠ ˆ261.9 (0.33, CH2Cl2);
nmax (KBr) 1776, 1748 cm21; dH (500 MHz, acetone-d6)
5.86 (d, 1H, J 3.5 Hz, H-1), 5.54 (dd, 1H, J 1.5, 3.0 Hz,
H-30), 5.11 (d, 1H, J 3.0 Hz, H-40), 4.52 (d, 1H, J 3.5 Hz,
H-2), 4.27±4.29 (m, 1H, H-3), 4.08±4.10 (m, 1H, H-4), 3.90
(d, 1H, J15.0 Hz, H-5b), 3.45 (ddd, 1H, J 1.5, 3.5, 15.0 Hz,
H-5a), 2.07 (s, 3H, Ac), 1.28, 1.41 (2s, 6H, isoprop.); HRMS
(EI) m/z: (MZCH3)1 found 284.0782. C12H14O7N requires
284.077.
3.1.14. (40S,40S) and (40R,40S) 5-Deoxy-3-O:5-C-[30-hy-
droxy-30-(1-hydroxy-1-methyl-ethyl)-azetidin-20-on-10,40-
di-yl]-1,2-O-isopropylidene-a-d-xylofuranose (30/31).
The mixture of stereoisomers 30/31, in a ratio ca. 6.4:1
(de 73%), was obtained from 15 according to the procedure
described for 29 (79%); [Found: C, 53.56; H, 7.00; N, 4.27.
C14H21O7N (315.33) requires C, 53.33; H, 6.71; N, 4.44%];
nmax (KBr) 3455, 3367, 1769, 1759 cm21; 30 (major
isomer): dH (500 MHz, acetone-d61D2O) selective signals
taken from the spectrum of the mixture: 5.90 (d, 1H, J
4.0 Hz, H-1), 4.94 (s, 1H, H-40), 4.66 (d, 1H, J 4.0 Hz,
H-2), 4.30±4.32 (m, 1H, H-3), 4.12±4.14 (m, 1H, H-4),
3.92 (d, 1H, J 15.0 Hz, H-5b), 3.52 (dd, 1H, J 4.0,
15.0 Hz, H-5a).
3.1.18. (40S) 5-Deoxy-3-O:5-C-[30-hydroxyimino-azeti-
din-20-on-40-yl]-1,2-O-isopropylidene-a-d-xylofuranose
(39). To the crude oil containing 35/36 (0.058 g) dissolved
in dry pyridine (2 mL), NH2OH´HCl (0.031 g, 0.45 mmol)
was added and the solution was stirred at room temperature
for 3 days. Subsequently, water was added and the aqueous
layer was extracted with EtOAc, dried (Na2SO4) and evapo-
rated. The residue was puri®ed by chromatography on silica
gel, using EtOAc/hexane 2:3 v/v as an eluent, to give the
title compound 39 as a mixture of syn and anti isomers
(0.023 g, ,50%). White solid; nmax (CH2Cl2) 3568, 1787,
1744 cm21; 39 (major isomer): dH (500 MHz, acetone-d6)
selective signals taken from the spectrum of the mixture:
11.41 (br s, 1H, ZOH), 5.85 (d, 1H, J 3.5 Hz, H-1), 5.63 (s,
1H, H-40), 4.53 (d, 1H, J 3.5 Hz, H-2), 4.04 (d, 1H,
J15.0 Hz, H-5b), 3.67 (dd, 1H, J 4.0, 15.0 Hz, H-5a).
31 (minor isomer): dH (500 MHz, acetone-d61D2O) selec-
tive signals taken from the spectrum of the mixture: 5.98 (d,
1H, J 3.5 Hz, H-1), 5.03 (s, 1H, H-40), 4.60 (d, 1H, J 3.5 Hz,
H-2), 4.35±4.37 (m, 1H, H-3), 4.09±4.11 (m, 1H, H-4), 3.89
(d, 1H, J 15.0 Hz, H-5b), 3.44 (dd, 1H, J 3.5, 15.0 Hz,
H-5a); HRMS (EI) m/z: M1 found 315.1316. C14H21O7N
requires 315.1318.
3.1.15. (40S) 3-O:5-C-[Azetidin-20,30-dion-10,40-di-yl)-5-
deoxy-1,2-O-isopropylidene-a-d-xylofuranose and (40S)
5-Deoxy-3-O:5-C-[30,30-dihydroxy-azetidin-20-on-10,40-
di-yl]-1,2-O-isopropylidene-a-d-xylofuranose (35) and
(36). The mixture of 35/36 was obtained from the mixture
of stereoisomers 30/31 according to the procedure described
for 32; nmax (KBr): 3420, 1794, 1762cm21; 35: dH (500
MHz, acetone-d6) 5.87 (d, 1H, J 4.0 Hz, H-1), 5.61 (s, 1H,
H-40), 4.55 (d, 1H, J 4.0 Hz, H-2), 4.44 (d, 1H, J 1.5 Hz,
H-3), 4.29 (d, 1H, J 15.0 Hz, H-5b), 4.20±4.21 (m, 1H,
H-4), 4.03 (dd, 1H, J 3.5, 15.0 Hz, H-5a), 1.28, 1.42 (2s,
6H, isoprop.).
39 (minor isomer): dH (500 MHz, acetone-d6) selective
signals taken from the spectrum of the mixture: 11.40 (br
s, 1H, ZOH), 5.87 (d, 1H, J 4.0 Hz, H-1), 5.40 (s, 1H, H-40),
4.03 (d, 1H, J15.0 Hz, H-5b); HRMS (EI) m/z: (MZCH3)1
found 255.0592. C10H11O6N2 requires 255.0617.
3.1.19. (30R,40S) 3-O:5-C-[30-Acetylamino-azetidin-20-
on-40-yl]-5-deoxy-1,2-O-isopropylidene-a-d-xylofura-
nose (40). A solution of 39 (0.014 g, 0.052 mmol), AcONa
(0.0072 g, 0.088 mmol) and Ac2O (0.03 mL) in AcOEt
(0.5 mL) was stirred at room temperature for 14 h. An
additional AcOEt (5 mL) and PtO2 (0.005 g) was added to
the solution, and the mixture was stirred under 30 psi of H2
for 12 h. After the catalyst was ®ltered off, the ®ltrate was
concentrated under reduced pressure. The residue was
puri®ed by chromatography on silica gel eluted with
36: dH (500 MHz, acetone-d6) 5.90 (d, 1H, J 3.5 Hz, H-1),
5.55 (s, 1H, H-40), 4.59 (d, 1H, J 3.5 Hz, H-2), 4.53 (d, 1H, J
1.5 Hz, H-3), 4.24±4.26 (m, 1H, H-4), 4.18 (d, 1H, J
15.0 Hz, H-5b), 3.79 (dd, 1H, J 3.0, 15.0 Hz, H-5a), 2.78
(br s, 1H, ZOH), 1.29, 1.43 (2s, 6H, isoprop.). Due to low

R. èysek et al. / Tetrahedron 57 (2001) 1301±1309
1309
L.; Nguyen, H. K.; Carver, Ch. C. J. Med. Chem. 1995, 38,
1022±1034. (b) Buynak, J. D.; Doppalapudi, V. R.; Frotan,
M.; Kumar, R. Tetrahedron Lett. 1999, 40, 1281±1284.
AcOEt/hexane 8:2 v/v, to give the title compound 40
(0.01 g, 65%). White crystals; mp 284±2898C;
22
‰aŠ ˆ211.4 (0.3, MeOH); nmax (CHCl3) 3448, 1780,
D
1686 cm21; dH (500 MHz, CDCl3) 5.97 (br d, 1H, J
9.5 Hz, NH), 5.92 (d, 1H, J 3.5 Hz, H-1), 5.50 (ddd, 1H, J
1.5, 3.5, 9.5 Hz, H-30), 4.96 (d, 1H, J 3.5 Hz, H-40), 4.57 (d,
1H, J 3.5 Hz, H-2), 4.19 (d, 1H, J 1.5 Hz, H-3), 4.07±4.09
(m, 1H, H-4), 4.08 (d, 1H, J15.0 Hz, H-5b), 3.29 (ddd, 1H, J
1.5, 4.0, 15.0 Hz, H-5a), 2.04 (s, 3H, Ac), 1.33, 1.50 (2s, 6H,
isoprop.); HRMS (EI) m/z: M1 found 298.1168.
C13H18O6N2 requires 298.1165.
Â
13. èysek, R.; Furman, B.; KaøuzÇa, Z.; Frelek, J.; Suwinska, K.;
Â
Urbanczyk-Lipkowska, Z.; Chmielewski, M. Tetrahedron:
Asymmetry 2000, 11, 3131±3150.
14. KaøuzÇa, Z.; Furman, B.; Patel, M.; Chmielewski, M.
Tetrahedron: Asymmetry 1995, 5, 2179±2186.
15. Hoover, J. R. E. In Antibiotics II, Demain, A. L., Solomon,
N. A., Eds.; Springer: Berlin, 1983; pp 186.
16. Dalton, D. R.; Dutta, V. P.; Jones, D. C. J. Am. Chem. Soc.
1968, 90, 5498±5501.
17. (a) Natsugari, H.; Matsushita, Y.; Tamura, N.; Yoshioka, K.;
Ochiai, M. J. Chem. Soc., Perkin Trans. 1 1983, 403±411.
(b) Aratani, M.; Hirai, H.; Sawada, K.; Yamada, A.;
Hashimoto, M. Tetrahedron Lett. 1985, 26, 223±226.
18. (a) Nakayama, M.; Iwasaki, A.; Kimura, S.; Mizoguchi, T.;
Tanabe, S.; Murakami, A.; Watanabe, I.; Okuchi, M.; Itoh, H.;
Saino, Y.; Kobayashi, F.; Mori, T. J. Antibiot. 1980, 33, 1388±
1390. (b) Imada, A.; Nozaki, Y.; Kintaka, K.; Okonogi, K.;
Kitano, K.; Harada, S. J. Antibiot. 1980, 33, 1417±1424.
(c) Harada, S.; Shinagawa, S.; Nozaki, Y.; Asai, M.; Kishi,
T. J. Antibiot. 1980, 33, 1425±1430.
Acknowledgements
The authors wish to thank the State Committee for Scienti®c
Research Grant No. T 09/PBZ.6.04 for support of this work.
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