Stereocontrolled formation of oxacephams from carbohydrates

Article abstract of DOI:10.1016/S0008-6215(02)00139-8

The [2+2] cycloaddition of chlorosulfonyl isocyanate to (Z)-4-O-propenyl ethers 16, 17, 29 and 30 proceeds with an excellent stereoselectivity in the case of ether 16 and with moderate stereoselectivity in remaining cases. Adducts were transformed into corresponding oxacephams: 37 in the first case, a mixture of 37/40 in the second and third case, and a mixture of 50/51 in the last case. In all instances addition to the si-re side of the olefin dominates. Oxacephams 41 and 52 with opposite R-configuration at the bridgehead carbon C-5a can be obtained by the alternate methodology based on the alkylation of nitrogen in 4-vinyloxyazetidin-2-one by protected 6-O-triflate 24 or 25, followed by cyclization via intramolecular displacement of the vinyloxy group. Compounds 37, 40, 41, 50, 51 and 52 constitute a convenient entry leading to polyfunctionalized oxacephams.

Full text of DOI:10.1016/S0008-6215(02)00139-8

Carbohydrate Research 337 (2002) 2005–2015
www.elsevier.com/locate/carres
Stereocontrolled formation of oxacephams from carbohydrates
Katarzyna Borsuk,a Arkadiusz Kazimierski,a Jolanta Solecka,b
Zofia Urban´czyk-Lipkowska,a Marek Chmielewskia,*
aInstitute of Organic Chemistry, 01-224 Warsaw, Poland
bInstitute of Hygiene, 00-791 Warsaw, Poland
Received 30 April 2002; accepted 7 June 2002
Dedicated to Professor Derek Horton on the occasion of his 70th birthday
Abstract
The [2+2] cycloaddition of chlorosulfonyl isocyanate to (Z)-4-O-propenyl ethers 16, 17, 29 and 30 proceeds with an excellent
stereoselectivity in the case of ether 16 and with moderate stereoselectivity in remaining cases. Adducts were transformed into
corresponding oxacephams: 37 in the first case, a mixture of 37/40 in the second and third case, and a mixture of 50/51 in the
last case. In all instances addition to the si–re side of the olefin dominates. Oxacephams 41 and 52 with opposite R-configuration
at the bridgehead carbon C-5a can be obtained by the alternate methodology based on the alkylation of nitrogen in
4-vinyloxyazetidin-2-one by protected 6-O-triflate 24 or 25, followed by cyclization via intramolecular displacement of the
vinyloxy group. Compounds 37, 40, 41, 50, 51 and 52 constitute a convenient entry leading to polyfunctionalized oxacephams.
© 2002 Elsevier Science Ltd. All rights reserved.
Keywords: [2+2] Cycloaddition; Chlorosulfonyl isocyanate; 4-O-Propenyl-hexopyranosides; 4-O-Vinyloxyazetidin-2-one; Oxacephams
tive to the above cycloaddition method, based on the
alkylation of the nitrogen atom in 4-vinyloxyazetidin-2-
one (5) by a structurally akin sugar fragment, followed
by an intramolecular displacement of the vinyloxy
group, leads to oxacephams with the opposite configu-
ration at the C-6 carbon atom.7,8 These two comple-
mentary methods are exemplified in Scheme 1 by the
1. Introduction
In previous papers,1–3 we have shown that [2+2]
cycloaddition of chlorosulfonyl isocyanate (CSI) to 3-
O-and 5-O-vinyl ethers of 1,2-O-isopropylidene-a-D-
glucofuranose proceeds in many cases with excellent
stereoselectivity and allows control of the configuration
at C-4 of the 4-alkoxyazetidin-2-one. The cycloadducts
offer an entry to clavams and 5-oxacephams via suit-
able transformation of the sugar fragment.4,5
transformation of 1,3-O-ethylidene- -erythritol (1) into
L
cephams 7–9.9 In the cycloaddition method, the pres-
ence of a large substituent at O-4, such as trityl, pro-
motes the exclusive formation of one stereoisomer 2,
which after N-alkylation yields oxacepham 7. Whereas,
if the less bulky substituent is present, such as mesyl,
then both possible diastereomeric products 3 and 4 are
formed, which then lead to the mixture of correspond-
ing cephams 7 and 8.9 The second methodology pro-
vides cepham 9 as a sole reaction product after
nucleophilic displacement at C-4 of the azetidin-2-one
ring in 6.
It has been shown by us6 that the [2+2] cycloaddi-
tion of chlorosulfonyl isocyanate (CSI) to sugar vinyl
ethers is sterically controlled. To assign the spatial
array of atoms in the transition state of the cycloaddi-
tion, s-trans conformation of the ether fragment should
be used. We have shown, in addition, that the alterna-
Abbre6iations: PMB, p-methoxybenzyl; TBDPS, tert-
butyldiphenylsilyl; TBS, tert-butyldimethylsilyl.
* Corresponding author. Tel.: +48 22 6323789; fax: +48
22 6326681
We expected that the presence of the rigid trans
trioxadecalin skeleton in compounds 7–9 would result
in angle strain and influence the geometry of the four-
E-mail address: chmiel@icho.edu.pl (M. Chmielewski).
0008-6215/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(02)00139-8

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K. Borsuk et al. / Carbohydrate Research 337 (2002) 2005–2015
Scheme 1.
membered b-lactam ring. Bearing in mind that the
configuration at C-6 in the cephams is essential for their
biological activity,10 it was of interest to synthesize
compounds that would be enantiomerically related to
7–9 within the cepham fragment and to examine their
potential biological activities.
2. Results and discussion
For the present study, we selected readily available
ethyl 2,3-dideoxy-
D
-erythro-hexoside (10) and methyl
The [2+2] cycloaddition of CSI to 16, followed by the
reduction of the N-chlorosulfonyl group of the adduct
with bis-(2-methoxyethoxy)aluminum hydride (Red-Al,
Aldrich), led to the b-lactam 33 as a sole product in 54%
yield. The trityl protecting group in 33 was then removed
cleanly by treatment with sodium in liquid ammonia to
give 34 in 85% yield. The hydroxy group in 34 was
subsequently tosylated under standard conditions af-
fording 35. Intramolecular alkylation of the b-lactam
nitrogen atom in 35 using a two-phase system led to
oxacepham 37 in 86% yield. The molecular structure
assignment and 6S-configuration of 37 was proved by
NOE measurement between H-4 and H-6. The lack of
any spin–spin interaction between both protons indi-
cated their anti arrangement. The NMR assignment has
been also supported by CD spectroscopy.11
2,3-di-O-benzyl- -glucoside (11). Compounds 10 and 11
D
were transformed into derivatives 16 and 17, respec-
tively, by standard methods,9 while the corresponding
tosylate 29 and mesylate 30 were obtained by a similar
standard reaction sequence from compound 26. It is
worth noting that rearrangement of the allyl ether 27 in
the presence of a large excess of potassium tert-butoxide
(4 times molar equiv) caused simultaneous 6-O-desilyla-
tion. The Z configuration of propenyl ethers 16, 17, and
28–30 was assigned on the basis of the vicinal coupling
constants between olefinic protons (J 6.2 Hz).
The cycloaddition performed with 29 gave two corre-
sponding azetidin-2-ones 35 and 38 in a ratio of 1.5:1,
respectively, in 65% yield. The same reaction carried out
using mesylate 30 yielded diastereomers 36 and 39 in a
ratio of 1.6:1, respectively. These results indicate the
existence of a steric control during cycloaddition. In-
tramolecular alkylation of the nitrogen atom carried out
with either mixtures 35/38 or 36/39 led to oxacephams
37 and 40. In both instances, the proportion of isomeric
cephams 37 and 40 remained the same as in the sub-
strates 35/38 and 36/39. Chromatographic separation of
37 and 40 allowed one to characterize cepham 40

K. Borsuk et al. / Carbohydrate Research 337 (2002) 2005–2015
2007
Table 1
Crystal data and structure refinement for compound 41a
Empirical formula
Formula weight
C11H17NO4
227.26
Crystal system, space group
orthorhombic,
P212121
,
Unit cell dimensions (A)
a
b
4.9595(2)
8.7112(7)
c
27.1774(17)
1174.15(13)
4, 1.286
0.814
488
3
,
Volume (A )
Z, calculated density (Mg m−3
)
Fig. 1. X-Ray structure of compound 41a with crystallo-
graphical numbering scheme.
Absorption coefficient (mm−1
F(000)
)
q range for data collection (°)
Reflections collected/unique
3.25–73.86
1438/1138
[R(int)=0.0430]
99.93 and 89.60
1138/0/147
1.118
in which H-4 and H-6 show NOE effects, indicating
presence of the cis arrangement of both protons.
Analogously to cepham 37, the NMR assignment made
for 40 was also supported by the CD spectroscopy.11
Max. and min. transmission
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I\2|(I)]
R1=0.0559,
wR2=0.1763
0.7(6)
Absolute structure parameter
Extinction coefficient
0.008(2)
Largest difference peak and hole
0.255 and −0.270
−3
,
(e A
)
tion at the acetal center (C-2) of the product. The
structure and configuration of crystalline compound 41a
was proved by the single-crystal X-ray analysis (Fig. 1,
Table 1).10 Partial hydrolysis of the acetal moiety in 37,
followed by the oxidation of resulting hemiacetal, yielded
lactone 42, which does offer an entry to the related
cephams with a side chain at C-4 (side chains that are
located in a related position are present in many natural
clavams 4312).
The [2+2] cycloaddition of CSI to the propenyl ether
17 proceeded in a high yield (89%) and with a low
stereoselectivity to give diastereomer 44 with 50% de.
Both equatorial substituents in the vicinity of the pro-
penyl ether fragment shield diastereotopic faces of the
olefin, but the presence of the bulky trityloxymethyl
group played a decisive role in the direction of asymmetric
induction.
Stereocontrolled formation of the 6R-configuration in
the same strained tricyclic skeleton can be achieved by
the second methodology as outlined above. Starting
triflate 24 was obtained from compound 10 by a standard
sequence of reactions involving silylation of the terminal
group, protection of the secondary hydroxy group in 18
by a p-methoxybenzyl residue, desilylation of 20 leading
to 22, and finally the formation of triflate 24. Alkylation
of 4-vinyloxyazetidin-2-one 5 with the triflate 24 gave
mixture of diastereomers 31, which was treated with a
Lewis acid to give cephams 41. Acidic conditions that
were necessary during the intramolecular substitution at
C-4% of the azetidin-2-one ring caused partial epimeriza-

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K. Borsuk et al. / Carbohydrate Research 337 (2002) 2005–2015
produced as a sole product compound 52 with the
R-configuration at C-6. Benzylic groups in 52 were
removed by hydrogenolysis to provide hydrophilic
cepham 53 which was characterized as diacetate 54.
Selected tricyclic b-lactams 7, 8, 9, 37, 40, 41a, and
41b were evaluated for their biological activities. An
inhibition of the DD-carboxypeptidase activity was
measured.13,14 Compounds 9, 37, and 40 showed slight
activity (20–30% inhibition) at a concentration of 10−3
M. We were not able to find any significant differences
between the biological activities of tested compounds,
and, therefore, at this level of inhibition, structure–ac-
tivity relationships could not be defined.
3. Conclusions
It was demonstrated that the configuration at the
bridgehead carbon atom (C-5a), which is important for
the biological activity of b-lactam antibiotics, could be
controlled by the selection of strategy used for oxa-
cepham formation. The [2+2] cycloaddition method
led to diastereomers with the S-configuration at C-5a,
whereas the cyclization method provided compounds
with an alternative R-configuration at that center. The
latter proceeded with better stereoselectivity, particu-
larly for chiral substrates in which diastereotopic faces
of the vinyl ether were similarly shielded. The trans-
fused ring system provides a rigid template that intro-
duces an alternation of geometry of the b-lactam ring.
This, however, was not reflected in the extent of mea-
sured biological activity of the products. It was shown
that the sugar fragments in the synthesized tricyclic
b-lactams can readily be subjected to further
transformations.
4. Experimental
Melting points were determined on a Koefler hot-
1
stage apparatus. H NMR spectra were recorded using
Brucker Avance 500 and Varian Mercury 400 instru-
ments. IR spectra were recorded on a Perkin–Elmer
FTIR Spectrum 200 spectrophotometer. Mass spectra
were recorded using AMD-604 Inectra GmbH and
HPLC–MS with Mariner and API 356 detectors. Opti-
cal rotations were measured using a Jasco P 3010
polarimeter at 2293 °C. Column chromatography was
performed using E. Merck Kiesel Gel (230–400 mesh).
Compounds 12,15 13,16 1517 and 1918 were obtained
following the indicated literature procedures.
Mixture 44/45 was detritylated, the free terminal
hydroxy group was subsequently tosylated, and the
resulting tosylates 48/49 were in turn subjected to the
intramolecular alkylation of the nitrogen atom leading
to oxacephams 50/51, which were separated by chro-
matography into the pure components. The configura-
tion of compounds 51 and 52 was indicated by NOE
measurements between the H-4a and H-5a protons.
Compound 51 displayed a spin–spin interaction be-
tween both protons, whereas diastereomeric compound
50 did not show any interactions.
Methyl 2,3-di-O-benzyl-6-O-trityl-h-D-glucopyran-
oside (13).—The compound was obtained following the
literature procedure16 (98%). Foam; [h]D +31.5° (c 0.9,
1
CH2Cl2); IR (film): wmax 3472 cm−1 (OH); H NMR
The second methodology when applied to the b-lac-
tam 33, which is readily available from glycoside 11,
(CDCl3): l 7.46–7.20 (m, 25 H, trityl, benzyl), 4.96,

K. Borsuk et al. / Carbohydrate Research 337 (2002) 2005–2015
2009
4.74 (2 d, 2 H, J 11.3 Hz, Bn), 4.78, 4.68 (2 d, 2 H, J
12.1 Hz, Bn), 4.67 (d, 1 H, J 3.6 Hz, H-1), 3.69 (ddd, 1
H, J 3.6, 5.2, 9.3 Hz, H-5), 3.77 (t, 1 H, J 9.2 Hz, H-3),
3.55 (ddd, 1 H, J 2.4, 9.7, 9.7 Hz, H-4), 3.52 (dd, 1 H,
J 3.6, 9.6, H-2), 3.42 (s, 3 H, OCH3), 3.35 (dd, 1 H, J
3.5, 10.0 Hz, H-6), 3.29 (dd, 1 H, J 5.3, 10.0 Hz, H-6%),
2.23 (d, 1 H, J 2.5 Hz, OH); ESIHRMS: Calcd for
C40H40NaO6: 639.2718; found: m/z 639.2717 [M+
Na]+.
NMR (CDCl3): l 7.50–7.19 (m, 15 H, trityl), 5.86 (dq,
1 H, J 6.2, 1.7 Hz, H-1%), 4.88 (bd, 1 H, J 3.2 Hz, H-1),
4.20 (dq, 1 H, J 6.2, 6.7 Hz, H-2%), 3.88–3.81 (m, 2 H,
H-5, Et), 3.63 (dt, 1 H, J 4.9, 9.8 Hz, H-4), 3.52 (dq, 1
H, Et), 3.35 (dd, 1 H, J 1.9, 9.9 Hz, H-6a), 3.16 (dd, 1
H, J 5.5, 9.9 Hz, H-6b), 1.96–1.73 (m, 4 H, H-
2,2a,3,3a), 1.33 (dd, 3 H, J 1.6, 6.7 Hz, CH3), 1.26 (t, 3
H, Et); ESIHRMS: Calcd for C30H34NaO4: 481.2349;
found: m/z 481.2361 [M+Na]+.
Methyl 2,3-di-O-benzyl-(Z)-4-O-propenyl-6-O-trityl-
Ethyl 4-O-allyl-2,3-dideoxy-6-O-trityl-h-D-erythro-
h- -glucopyranoside (17).—Compound 17 was ob-
D
hexopyranoside (14).—To a solution of compound 12
(0.97 g, 2.3 mmol) in dry toluene (10 mL) powdered
KOH (0.14 g, 2.5 mmol) was added. The suspension
was stirred for 20 min, and then allyl bromide (0.17
mL, 2.7 mmol) and 0.02 g Bu4NBr were added. Stirring
was continued for 2 h until disappearance of the sub-
strate was indicated (TLC). The mixture was then
filtered through Celite, and the solvent was evaporated.
The residue was purified by column chromatography
using 9:1 hexane–ethyl acetate as an eluant to give
product 14 (0.72 g, 72%). Colorless oil; [h]D +85.7° (c
tained from 15 following the procedure described for 16
(85%). Colorless foam; [h]D +42.4° (c 0.8, CH2Cl2); IR
1
(film): wmax 1668 cm−1 (ꢀCH-O-); H NMR (CDCl3): l
7.46–7.18 (m, 25 H, trityl, benzyl), 5.97 (dq, 1 H, J 6.2,
1.7 Hz, H-1%), 4.83, 4.71 (2 d, 2 H, J 12.2 Hz, Bn), 4.79,
4.74 (2 d, 2 H, J 10.5 Hz, Bn), 4.73 (d, 1 H, J 3.6 Hz,
H-1), 4.14 (dq, 1 H, J 6.2, 6.8 Hz, H-2%), 3.90 (dd, 1 H,
J 8.6, 9.8 Hz, H-3), 3.79 (ddd, 1 H, J 1.7, 4.4, 10.0 Hz,
H-5), 3.75 (dd, 1 H, J 8.5, 10.0 Hz, H-4), 3.57 (dd, 1 H,
J 3.6, 9.6 Hz, H-2), 3.44 (s, 3 H, OCH3), 3.37 (dd, 1 H,
J 1.7, 10.2 Hz, H-6), 3.26 (dd, 1 H, J 4.4, 10.2 Hz,
H-6%); ESIHRMS: Calcd for C43H44NaO6: 679.3035;
found: m/z 679.3057 [M+Na]+.
1
0.8, CH2Cl2); H NMR (CDCl3): l 7.51–7.19 (m, 15 H,
trityl), 5.66 (m, 1 H, H-2%), 5.04 (m, 1 H, H-3%a), 5.01
(m, 1 H, H-3%b), 4.87 (bs, 1 H, H-1), 3.94, 3.73 (2 m, 2
H, H-1%a, 1%b), 3.83, 3.51 (2 dq, 2 H, Et), 3.78 (ddd, 1
H, J 1.9, 5.2, 9.5 Hz, H-5), 3.39 (bdt, 1 H, J 4.9, 9.5,
11.1 Hz, H-6b), 1.98–1.71 (m, 4 H, H-2a, 2b, 3a, 3b),
1.24 (t, 3 H, Et); ESIHRMS: Calcd for C30H34NaO4:
481.2349; found: m/z 481.2343 [M+Na]+.
Ethyl
6-O-tert-butyldiphenylsilyl-2,3-dideoxy-h-D-
erythro-hexopyranoside (18).—Compound 18 was ob-
tained from 10 following standard silylation procedures
(98%). Colorless oil; [h]D +43.8° (c 0.6, CH2Cl2); IR
(film): wmax 3470 cm−1 (OH); 1H NMR (CDCl3): l
7.71–7.37 (m, 10 H, 2 Ph), 4.71 (bd, 1 H, J 2.9 Hz,
H-1), 3.83 (dd, 1 H, J 4.8, 10.3 Hz, H-6), 3.81 (dd, 1 H,
J 6.1, 10.3 Hz, H-6%), 3.66 (dt, 1 H, J 4.9, 9.2 Hz, H-4),
3.63 (m, 1 H, H-5), 3.59, 3.37 (2 dq, 2 H, Et), 1.90–1.62
(m, 4 H, H-2,2%,3,3%), 1.18 (t, 3 H, Et), 1.07 (s, 9 H,
t-Bu); ESIHRMS: Calcd for C24H34NaO4Si: 437.2119;
found: m/z 437.2143 [M+Na]+.
Methyl
4-O-allyl-2,3-di-O-benzyl-6-O-trityl-h-D-
glucopyranoside (15).—The compound was obtained
following the literature procedure17 (94%). Foam; [h]D
1
+43.1° (c 1.2, CH2Cl2); H NMR (CDCl3): l 7.46–
7.20 (m, 25 H, trityl, benzyl), 5.53 (m, 1 H, H-2%), 4.97
(m, 2 H, H-3%a,b), 4.90, 4.82 (2 d, 2 H, J 12.1 Hz, Bn),
4.77, 4.71 (2 d, 2 H, J 10.7 Hz, Bn), 4.74 (d, 1 H, J 3.6
Hz, H-1), 4.10 (qt, 1 H, J 1.4, 5.9 Hz, H-1%a), 3.88 (t, 1
H, J 9.3 Hz, H-3), 3.76 (qt, 1 H, J 1.4, 5.8 Hz, H-1%b),
3.72 (ddd, 1 H, J 2.0, 4.5, 9.5 Hz, H-5), 3.58 (dd, 1 H,
J 3.6, 9.6, H-2), 3.47 (dd, 1 H, J 9.0, 9.9 Hz, H-4), 3.44
(s, 3 H, OCH3), 3.41 (dd, 1 H, J 2.0, 10.1 Hz, H-6), 3.11
(dd, 1 H, J 4.6, 10.1 Hz, H-6%); ESIHRMS: Calcd for
C43H44NaO6: 679.3035; found: m/z 679.3069 [M+
Na]+.
Ethyl 6-O-tert-butyldiphenylsilyl-2,3-dideoxy-4-O-p-
methoxybenzyl-h- -erythro-hexopyranoside (20).—To a
D
solution of compound 18 (0.7 g, 1.7 mmol) in dry
toluene (10 mL) powdered KOH (0.114 g, 2.04 mmol)
was added. The resulting suspension was stirred for 20
min, and then p-MeOC6H4CH2Cl (0.28 mL, 2.04
mmol) and 0.04 g Bu4NBr was added. Stirring was
continued for 2 h until disappearance of the substrate
was indicated (TLC). The mixture was then filtered
through Celite, and the solvent was evaporated. The
residue was purified by column chromatography using
9:1 hexane–EtOAc as the eluant to give the product 20
(0.69 g, 70%). Colorless oil; [h]D +76.1° (c 0.5,
Ethyl 2,3-dideoxy-(Z)-4-O-propenyl-6-O-trityl-h-D-
erythro-hexopyranoside (16).—The solution of allyl
ether 14 (0.7 g, 1.55 mmol) and freshly sublimed t-
BuOK (1.7 mmol) in DMSO (10 mL) was left standing
for 1.5 h (TLC monitoring) at 50 °C. Subsequently, the
mixture was poured into satd aq NaCl and extracted
with t-BuOMe (3×25 mL). The organic layer was
washed with water, dried (MgSO4) and concentrated.
The residue was purified by column chromatography
using 95:5 hexane–EtOAc as the eluant to give the
product 16 (0.608 g, 86%). Colorless oil; [h]D +11.3° (c
0.2, CH2Cl2); IR (CHCl3): wmax 1667 cm−1 (CꢀC-O); 1H
1
CH2Cl2); H NMR (CDCl3): l 7.75–7.34 (m, 10 H, 2
Ph), 7.13, 6.81 (2 m, 4 H, -C6H4-), 4.83 (bd, 1 H, J 3.0
Hz, H-1), 4.54, 4.35 (2 d, 2 H, J 11.1 Hz, ArCH2), 3.79
(s, 3 H, OCH3), 3.77, 3.46 (2 dq, 2 H, Et), 3.74 (m, 1 H,
H-5), 3.46 (m, 1 H, H-42.05–1.66 (m, 4 H, H-2,2%,3,3%),
1.21 (t, 3 H, Et), 1.06 (s, 9 H, t-Bu); ESIHRMS: Calcd
for C32H42NaO5Si: 557.2694; found: m/z 557.2701
[M+Na]+.

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K. Borsuk et al. / Carbohydrate Research 337 (2002) 2005–2015
Methyl 2,3-di-O-benzyl-4-O-p-methoxybenzyl-6-O-
triflyl-h- -glucopyranoside (25).—Compound 25 was
obtained from 23 following procedure described for 24
Methyl 2,3-di-O-benzyl-6-O-tert-butyldimethylsilyl-4-
D
O-p-methoxybenzyl-h- -glucopyranoside (21).—Com-
D
pound 21 was obtained from known compound 1918
(80%) and used in the next step as a crude yellow oil.
according to the procedure described for 20 (95%).
1
Ethyl
6-O-tert-butyldimethylsilyl-2,3-dideoxy-h-D-
Colorless oil; [h]D +22.3° (c 1.7, CH2Cl2); H NMR
erythro-hexopyranoside (26).—Compound 26 was ob-
tained form 10 following standard silylation procedure
(96%). Colorless oil; [h]D +183.5° (c 1.0, CH2Cl2); IR
(CDCl3): l 7.38–7.26 (m, 20 H, 2 Ph, benzyl), 7.20,
6.85 (2 m, 4 H, C6H4), 4.97, 4.67 (2 d, 2 H, J 10.8 Hz,
Bn), 4.80, 4.57 (2 d, 2 H, J 10.6 Hz, Bn), 4.78, 4.67 (2
d, 2 H, J 12.0 Hz, Bn), 4.60 (d, 1 H, J 3.6 Hz, H-1),
3.97 (dd, 1 H, J 8.9, 9.6 Hz, H-3), 3.79 (s, 3 H, OCH3),
3.77 (dd, 1 H, J 2.6, 11.3 Hz, H-6), 3.75 (dd, 1 H, J 3.8,
11.3 Hz, H-6%), 3.59 (ddd, 1 H, J 2.6, 3.8, 9.8 Hz, H-5),
3.49 (dd, 1 H, J 8.9, 9.8 Hz, H-4), 3.48 (dd, 1 H, J 3.6,
9.6 Hz, H-2), 3.36 (s, 3 H, OCH3), 0.89, 0.05, 0.04 (3 s,
15 H, t-BuMe2Si); ESIHRMS: Calcd for C35H48O7-
NaSi: 631.3062; found: m/z 631.3070 [M+Na]+.
1
(film): wmax 3451 cm−1 (OH); H NMR (CDCl3): l 4.77
(bd, 1 H, J 3.1 Hz, H-1), 3.85 (dd, 1 H, J 4.4, 10.0 Hz,
H-6), 3.73, 3.69 (2 m, 2 H, H-6%, H-4), 3.63 (ddd, 1 H,
J 1.9, 4.7, 9.1 Hz, H-5), 3.46, 3.43 (2 dq, 2 H, Et), 3.29
(d, 1 H, J 1.5, OH), 1.87–1.65 (m, 4 H, H-2,2%,3,3%),
1.22 (t, 3 H, Et), 0.91 (s, 9 H, t-Bu), 0.1 (2 s, 6 H, Me);
ESIHRMS: Calcd for C14H30NaO4Si: 313.1824; found:
m/z 313.1806 [M+Na]+.
Ethyl 4-O-allyl-2,3-dideoxy-6-O-tert-butyldimethylsi-
Ethyl 2,3-dideoxy-4-O-p-methoxybenzyl-h-D-erythro-
lyl-h- -erythro-hexopyranoside (27).—Compound 27
D
hexopyranoside (22).—To a solution of 20 (0.6 g, 1.5
mmol) in dry THF (10 mL) TBAF (0.2 g, 1.65 mmol)
was added. The reaction was stirred for 20 h (TLC
monitoring). The mixture was subsequently evaporated,
and the residue was purified by column chromatogra-
phy using 3:2 hexane–EtOAc as the eluant to give the
product 22 (0.36 g, 83%). Colorless oil; [h]D +116.4° (c
0.7, CH2Cl2); IR (film): wmax 3470 cm−1 (OH); 1H
NMR (CDCl3): l 7.25, 6.87 (2 m, 4 H, -C6H4-), 4.78
(bd, 1 H, J 3.3 Hz, H-1), 4.58, 4.40 (2 d, 2 H, J 11.2 Hz,
ArCH2), 3.80 (s, 3 H, OCH3), 3.78 (dd, 1 H, J 3.4, 10.0
Hz, H-6), 3.70 (m, 3 H, H-5,6,OCHAHBCH3), 3.42 (m,
2 H, H-5,6,OCHAHBCH3), 2.04–1.62 (m, 4 H, H-
2,2%,3,3%), 1.20 (t, 3 H, Et), 1.07 (s, 9 H, t-Bu); ES-
IHRMS: Calcd for C16H24NaO5: 319.1516; found: m/z
319.1521 [M+Na]+.
was obtained from 26 following the procedure de-
scribed for 14 (80%). Colorless oil; [h]D +109.6° (c 2.5,
CH2Cl2); 1H NMR (CDCl3): l 5.94 (m, 1 H, H-2%), 5.30
(dq, 1 H, J 17.2, 1.7 Hz, H-3%a), 5.18 (dq, 1 H, J 10.4,
1.3 Hz, H-3%b), 4.83 (d, 1 H, J 3.0 Hz, H-1), 4.14, 3.97
(2 m, 2 H, H-1%a,1%b), 3.87 (dd, 1 H, J 2.0, 11.1 Hz,
H-6a), 3.83 (dd, 1 H, J 5.0, 11.1 Hz, H-6b), 3.77, 3.47
(2 dq, 2 H, Et), 3.64 (ddd, 1 H, J 2.0, 3.0, 9.3 Hz, H-5),
3.36 (m, 1 H, H-4), 2.04–1.66 (m, 4 H, H-2,2a,3,3a),
1.24 (t, 3 H, CH3), 0.95, 0.11 (2 s, 15 H, TBS);
ESIHRMS: Calcd for C17H34NaO4Si: 353.2119; found:
m/z 353.2128 [M+Na]+.
Ethyl
2,3-dideoxy-(Z)-4-O-propenyl-h-D-erythro-
hexopyranoside (28).—A solution of allyl ether 27 (0.45
g, 1.4 mmol) and freshly sublimed t-BuOK (4.8 mmol)
in DMSO (10 mL) was left for 2 h (TLC monitoring) at
50 °C. The mixture was poured into satd aq NaCl and
extracted with t-BuOMe (3×10 mL). The organic
layer was washed with water, dried (MgSO4) and con-
centrated. The crude product 28 was used in the next
step without any purification.
Methyl 2,3-di-O-benzyl-4-O-p-methoxybenzyl-h-D-
glucopyranoside (23).—Known compound 2319 was ob-
tained from 21 following the procedure described for 22
(98%).
Ethyl 2,3-dideoxy-4-O-p-methoxybenzyl-6-O-triflyl-
h-D-erythro-hexopyranoside (24).—2,6-Lutidine (0.16
Ethyl 2,3-dideoxy-(Z)-4-O-propenyl-6-O-tosyl-h-D-
erythro-hexopyranoside (29).—Compound 29 was ob-
tained from 28 following the procedure described for 35
(70%). Colorless oil; [h]D +118.5° (c 0.9, CH2Cl2); IR
(CHCl3): wmax 1668 cm−1 (ꢀCH-O-); 1H NMR (CDCl3):
l 7.79, 7.32 (2 m, 4 H, C6H4), 5.85 (dq, 1 H, J 6.1, 1.7
Hz, H-1%), 4.73 (d, 1 H, J 3.2 Hz, H-1), 4.36 (dq, 1 H,
J 6.1, 6.8 Hz, H-2%), 4.23 (dd, 1 H, J 2.0, 10.5 Hz, H-6),
4.17 (dd, 1 H, J 5.0, 10.5 Hz, H-6%), 3.81 (ddd, 1 H, J
2.0, 5.0, 9.7 Hz, H-5), 3.64, 3.40 (2 dq, 2 H, Et), 3.48
(m, 1 H, H-4), 2.44 (s, 3 H, CH3), 2.0–1.62 (m, 4 H,
H-2,2a,3,3a), 1.46 (dd, 1 H, J 1.7, 6.8 Hz, CH3), 1.18 (t,
3 H, CH3); ESIHRMS: Calcd for C19H26NaO6S:
393.1342; found: m/z 393.1352 [M+Na]+.
mL, 1.3 mmol) was dissolved under argon in dry
CH2Cl2 (10 mL). Upon cooling to −20 °C, triflic anhy-
dride (0.21 mL, 1.3 mmol) was added dropwise. Stirring
was continued for 5 min, and then solution of com-
pound 22 (0.3 g, 1.0 mmol) in CH2Cl2 (1 mL) was
added dropwise. Stirring was continued at −20 °C for
5 min, then the solution was warmed up to 0 °C and
poured into ice-water (10 mL). The organic phase was
separated, washed with cold water (3×10 mL), dried
(MgSO4) and evaporated. The crude oil was dissolved
in t-BuOMe (ꢀ10 mL) and triturated with hexane
(ꢀ20 mL). The precipitate was filtered off through
Celite, and the filtrate was concentrated to give crude
triflate 24, which was immediately used for the subse-
quent step without further purification.
Ethyl 2,3-dideoxy-6-O-mesyl-(Z)-4-O-propenyl-h-D-
erythro-hexopyranoside (30).—To a solution of com-
pound 28 (0.11 g, 0.5 mmol) in dry pyridine (5 mL),

K. Borsuk et al. / Carbohydrate Research 337 (2002) 2005–2015
2011
MsCl (0.04 mL, 0.56 mmol) was added at 0 °C, and
mixture was left for 5 h at 20 °C. The reaction mixture
was diluted with water (15 mL) and extracted with
toluene (3×5 mL). Combined organic layers were
dried over MgSO4, filtered and concentrated to dryness.
The residue was purified by column chromatography
on a silica gel using 4:1 hexane–EtOAc as the eluant to
give the product 30 (0.1 g, 68%). Colorless oil; [h]D
+82.0° (c 0.4, CH2Cl2); IR (CHCl3): wmax 1668 cm−1
Ethyl 2,3-dideoxy-4-O-(3%R,4%S)-(3%-methylazetidin-
2%-on-4%-yl)-6-O-trityl-h- -erythro-hexopyranoside (33).
D
—To a suspension of anhyd Na2CO3 (0.26 g, 2.4 mmol)
in dry toluene (2.5 mL) chlorosulfonyl isocyanate (0.17
g, 1.95 mmol) was added. The mixture was stirred, and
upon cooling to −78 °C a solution of vinyl ether 16
(0.45 g, 0.98 mmol) in toluene (0.5 mL) was added
dropwise. Stirring was continued for 1.5 h, then the
mixture was diluted with toluene (3 mL), treated with
[(MeOCH2CH2O)2AlH2]Na (Red-Al, 1 M in toluene,
1.95 mL), and left for 30 min, continuously maintaining
a temperature of −78 °C. Subsequently, the tempera-
ture was allowed to rise to 0 °C, water (0.1 mL) was
added, and the solution was stirred for 15 min. The
mixture was filtered through Celite, and the solvent was
evaporated. The residue was purified by silica gel
column chromatography using 3:2 hexane–EtOAc. Ob-
tained 33 (0.26 g, 54%). Colorless crystals; mp 118–
120 °C; [h]D +51.0° (c 0.7, CH2Cl2); IR (CHCl3): wmax
1
(ꢀCH-O-); H NMR (CDCl3): l 5.97 (dq, 1 H, J 6.2,
1.7 Hz, H-1%), 4.81 (bd, 1 H, J 3.4 Hz, H-1), 4.47 (dq,
1 H, J 6.2, 6.8 Hz, H-2%), 4.43 (dd, 1 H, J 2.3, 11.1 Hz,
H-6), 4.40 (dd, 1 H, J 4.6, 11.1 Hz, H-6%), 3.92 (ddd, 1
H, J 2.3, 4.6, 9.7 Hz, H-5), 3.72, 3.46 (2 dq, 2 H, Et),
3.56 (m, 1 H, H-4), 3.03 (s, 3 H, CH3), 2.01–1.67 (m, 4
H, H-2,2a,3,3a), 1.66 (dd, 1 H, J 1.7, 6.8 Hz, CH3), 1.23
(t, 3 H, Et); ESIHRMS: Calcd for C12H22NaO6S:
317.1020; found: m/z 317.1033 [M+Na]+.
Ethyl
2,3,6-trideoxy-4-O-p-methoxybenzyl-6-C-
-erythro-
1
(4%R,4%S)-(4%-6inyloxyazetidin-2%-on-1%-yl)-h-
D
3411 (NH), 1770 cm−1 (CꢀO); H NMR (CDCl3): l
hexopyranoside (31).—To a stirred suspension of finely
powdered Bu4NHSO4 (0.19 g, 0.55 mmol) in dry THF
(10 mL) under argon was added 4-vinyloxyazetidin-2-
one (0.057 g, 0.5 mmol). Subsequently, upon cooling to
−78 °C, BuLi (0.56 mL of 2 M in hexane, 1.13 mmol)
was added, followed after 20 min by crude triflate 24
(ꢀ0.7 mmol) in dry THF (3 mL). Stirring was contin-
ued at −78 °C for 15 min. Subsequently, the mixture
was allowed to slowly warm up to room temperature
and stand for an additional 15 min. The reaction
mixture was poured into water (15 mL) and extracted
with t-BuOMe (3×10 mL). The combined organic
extracts were washed with water, dried (MgSO4) and
evaporated. The crude product was purified on silica
gel using 4:1 hexane–EtOAc as the eluant to give a
mixture 31 (0.15 g, 52%). Colorless oil; IR (film): wmax
1768 cm−1 (CꢀO); 1H NMR (CDCl3) selected signals of
both diastereomers: l 6.45 and 6.40 (2 dd, 1 H, J 6.6,
14.2 Hz, ꢀCHO- of both diastereomers), 5.38 and 5.34
(2 dd, 1 H, J 1.1, 3.6 Hz, H-4% of both diastereomers),
4.76 and 4.75 (2 dd, 1 H, J 2.9 Hz, H-1 of both
diastereomers), 3.80, 3.79 (2 s, 3 H, OCH3 of both
diastereomers); ESIHRMS: Calcd for C21H29NNaO6:
414.1887; found: m/z 414.1898 [M+Na]+.
7.50–7.20 (m, 15 H, trityl), 6.03 (bs, 1 H, NH), 4.90
(bd, 1 H, J 2.4 Hz, H-1), 4.85 (d, 1 H, J 4.4 Hz, H-4%),
3.83, 3.53 (2 dq, 2 H, Et), 3.78 (ddd, 1 H, J 1.8, 4.8, 9.5
Hz, H-5), 3.58 (m, 1 H, H-4), 3.38 (dd, 1 H, J 1.8, 9.9
Hz, H-6a), 3.09 (dd, 1 H, J 4.9, 9.9 Hz, H-6b), 2.93
(qdd, 1 H, J 7.6, 2.3, 4.4 Hz, H-3%), 2.0–1.75 (m, 4 H,
H-2,2a,3,3a), 1.26 (t, 3 H, Et), 1.04 (d, 1 H, J 7.6 Hz,
CH3); ESIHRMS: Calcd for C31H35NNaO5: 524.2407;
found: m/z 524.2406 [M+Na]+.
Ethyl 2,3-dideoxy-4-O-(3%R,4%S)-(3%-methylazetidin-
2%-on-4%-yl)-h- -erythro-hexopyranoside (34).—Com-
D
pound 33 (0.23 g, 0.46 mmol) in dry THF (1 mL) was
added to a stirred solution of sodium metal (0.106 g,
4.6 mmol) in NH3 (liq, 20 mL). The mixture was stirred
for 25 min at −70 °C, then solid NH4Cl (0.2 g) was
added to destroy excess NaNH2. After removing the
cooling bath, the solvent was evaporated, and the
residue was partitioned between water and THF. The
aqueous layer was extracted with EtOAc (3×10 mL).
The combined organic extracts were dried over MgSO4,
filtered and concentrated to dryness to give 34 (0.1 g,
85%) as a light-yellow oil. The product was used for the
next step without any further purification.
Ethyl 2,3-dideoxy-4-O-(3%R,4%S)-(3%-methylazetidin-
Methyl 2,3-di-O-benzyl-6-deoxy-4-O-p-methoxybenz-
2%-on-4%-yl)-6-O-tosyl-h-D-erythro-hexopyranoside (35).
yl-6-C-(4%R,4%S)-(4%-6inyloxyazetidin-2%-on-1%-yl)-h-
D
-
—To a solution of compound 34 (0.1 g, 0.39 mmol) in
dry pyridine (3 mL) TsCl (0.46 mmol) was added at
0 °C. After 20 h at 20 °C the reaction mixture was
diluted with water (5 mL) and extracted with toluene
(3×5 mL). The combined organic layers were dried
over MgSO4, filtered and concentrated to dryness. The
residue was purified by column chromatography on a
silica gel using 1:1 hexane–EtOAc as the eluant to give
35 (0.12 g, 75%). Colorless oil; [h]D +96.8° (c 0.4,
CH2Cl2); IR (film): wmax 3264 (NH), 1765 cm−1 (CꢀO);
1H NMR (CDCl3): l 7.79, 7.34 (2 m, 4 H, C6H4), 6.11
glucopyranoside (32).—A mixture 32 was obtained
from 25 according to the procedure described for 31
(72%). Colorless oil; IR (film): wmax 1769 cm−1 (CꢀO);
1H NMR (CDCl3) selected signals of both diaster-
eomers: l 6.42 and 6.34 (2 dd, 1 H, J 6.6, 14.2 Hz,
ꢀCHO- of both diastereomers), 5.34 and 5.30 (2 dd, 1
H, J 1.0, 3.6 Hz, H-4% of both diastereomers), 3.80, 3.79
(2 s, 3 H, OCH3 of both diastereomers); ESIHRMS:
Calcd for C34H39NNaO8: 612.2568; found: m/z
612.2555 [M+Na]+.

2012
K. Borsuk et al. / Carbohydrate Research 337 (2002) 2005–2015
(bs, 1 H, NH), 5.03 (d, 1 H, J 4.4 Hz, H-4%), 4.73 (bd,
1 H, J 3.0 Hz, H-1), 4.32 (dd, 1 H, J 3.9, 10.5 Hz,
H-6a), 4.09 (dd, 1 H, J 1.8, 10.5 Hz, H-6b), 3.78 (ddd,
1 H, J 1.8, 3.9, 9.5 Hz, H-5), 3.52 (m, 1 H, H-4), 3.62,
3.40 (2 dq, 2 H, Et), 3.28 (qdd, 1 H, J 7.6, 2.3, 4.4 Hz,
H-3%), 2.45 (s, 3 H, CH3), 2.0–1.64 (m, 4 H, H-
2,2a,3,3a), 1.18 (t, 3 H, Et), 1.12 (d, 3 H, CH3);
ESIHRMS: Calcd for C19H27NNaO7S: 436.1400;
found: m/z 436.1407 [M+Na]+.
(CDCl3) selected signals: l 6.18 (bs, 1 H, NH), 5.12 (d,
1 H, J 4.5 Hz, H-4%), 4.81 (bd, 1 H, J 3.2 Hz, H-1), 4.52
(dd, 1 H, J 3.8, 11.1 Hz, H-6a), 4.33 (dd, 1 H, J 1.9,
11.1 Hz, H-6b), 3.37 (qdd, 1 H, J 7.6, 2.4, 4.5 Hz, H-3%).
1
Compound 39: H NMR (CDCl3) selected signals: l
6.55 (bs, 1 H, NH), 5.13 (d, 1 H, J 4.2 Hz, H-4%), 4.82
(bd, 1 H, J 4.0 Hz, H-1), 4.65 (dd, 1 H, J 3.0, 11.0 Hz,
H-6a), 4.26 (dd, 1 H, J 1.9, 11.0 Hz, H-6b), 3.28 (qdd,
1 H, J 7.6, 2.2, 4.2 Hz, H-3%); ESIHRMS: Calcd for
C13H23NNaO7S: 360.1087; found: m/z 360.1105 [M+
Na]+.
(2S,4aS,5aS,6R,8aR) and (2S,4aS,5aR,6S,8aR) 2-
Ethoxy-1,5-dioxa-6-methyl-7a-azacyclobuta[b]decalin-
7-one (37) and (40).—A mixture of 37 and 40 was
obtained from 35 and 38 or from 36 and 39 following
procedure described for 37. Proportions of 37/40 were
the same as in the substrate used.
Compound 40: Oil; [h]D +10.0° (c 2.1, CH2Cl2); IR
(film): wmax 1770 cm−1 (CꢀO); 1H NMR (CDCl3): l
4.46 (bd, 1 H, J 3.2 Hz, H-2), 4.36 (d, 1 H, J 3.8 Hz,
H-5a), 4.03 (dd, 1 H, J 6.1, 12.8 Hz, H-8), 3.66 (m, 1 H,
J 6.1, 9.2, 10.1 Hz, H-8a), 3.42, 3.08 (2 dq, 2 H, Et),
2.90 (ddd, 1 H, J 4.3, 9.2, 11.4 Hz, H-4a), 2.84 (qdd, 1
H, J 1.6, 3.8, 7.5 Hz, H-6), 2.53 (ddd, 1 H, J 1.6, 10.1,
12.8 Hz, H-8%), 2.03–1.32 (m, 4 H, H-3,3%,4,4%), 1.11 (d,
1 H, J 7.5 Hz, CH3), 0.95 (t, 3 H, Et); ESIHRMS:
Calcd for C12H19NNaO4: 264.1206; found: m/z
264.1215 [M+Na]+.
(2S,4aS,5aR,8aR) and (2R,4aS,5aR,8aR) 2-Ethoxy-
1,5-dioxa-7a-azacyclobuta[b]decalin-7-one (41a) and
(41b).—To a stirred solution of 31 (0.1 g, 0.25 mmol)
in dry CH2Cl2 (10 mL) at 0 °C was added BF3·Et2O
(0.032 g, 0.25 mmol). The mixture was allowed to warm
up to room temperature and then maintained at this
temperature for 15 min (TLC control). Subsequently,
satd aq NaHCO3 (2 mL) was added, and stirring was
continued for 10 min. The organic phase was separated,
washed with water, and dried (MgSO4) and the solvent
was evaporated. The crude products were separated on
a silica gel column using 1:7:2 acetone–hexane–CH2Cl2
as the eluant to afford 41a (0.033 g, 41%) and 41b
(0.006 g, 7%).
(2S,4aS,5aS,6R,8aR) 1,5-Dioxa-2-ethoxy-6-methyl-
7a-aza-cyclobuta[b]decalin-7-one (37).—To a solution
of 35 (0.105 g, 0.25 mmol) in dry acetonitrile (10 mL)
was added Bu4NBr (0.1 g, 0.3 mmol) and K2CO3 (0.35
g). The mixture was heated under reflux for 3 h, cooled,
diluted with toluene (10 mL) and filtered. The solution
was washed with water (5 mL), dried over MgSO4,
filtered and concentrated to dryness. The residue was
purified by column chromatography on silica gel using
3:2 hexane–EtOAc as the eluant to give 37 (0.05 g,
77%). Oil; [h]D +26.8° (c 1.9, CH2Cl2); IR (film): wmax
1
1771 cm−1 (CꢀO); H NMR (C6D6): l 4.69 (d, 1 H, J
3.3 Hz, H-5a), 4.44 (bd, 1 H, J 3.2 Hz, H-2), 3.77 (m,
1 H, J 7.6, 9.0, 9.5 Hz, H-8a), 3.65 (dd, 1 H, J 9.0, 12.1
Hz, H-8), 3.47, 3.13 (2 dq, 2 H, Et), 3.31 (ddd, 1 H, J
4.8, 9.5, 11.1 Hz, H-4a), 3.02 (ddd, 1 H, J 1.8, 7.6, 12.1
Hz, H-8%), 2.77 (qdd, 1 H, J 1.8, 3.3, 7.6 Hz, H-6),
1.94-1.23 (m, 4 H, H-3,3%,4,4%), 1.07 (d, 1 H, J 7.6 Hz,
CH3), 1.03 (t, 3 H, Et); ESIHRMS: Calcd for
C12H19NNaO4: 264.1206; found: m/z 264.1222 [M+
Na]+.
Ethyl 2,3-dideoxy-4-O-(3%S,4%R)- and (3%R,4%S)-(3%-
methylazetidin-2%-on-4%-yl)-6-O-tosyl-h-D-erythro-hexo-
pyranoside (35) and (38).—A mixture 35 and 38 in a
ratio of 1.5:1, respectively, was obtained by addition of
CSI to 29 following procedure described for 33 (65%).
Spectral data taken for the mixture 35 and 38: IR
1
(film): wmax 3278 (NH), 1768 cm−1 (CꢀO); 35: H NMR
(CDCl3) selected signals: l 6.10 (bs, 1 H, NH), 5.04 (d,
1 H, J 4.5 Hz, H-4%), 4.81 (bd, 1 H, J 3.1 Hz, H-1), 4.32
(dd, 1 H, J 3.9, 10.5 Hz, H-6a), 4.10 (dd, 1 H, J 1.9,
10.5 Hz, H-6b), 1.19 (d, 3 H, J 7.5 Hz, CH3).
1
Compound 38: H NMR (CDCl3) selected signals: l
6.27 (bs, 1 H, NH), 4.91 (d, 1 H, J 4.3 Hz, H-4%), 4.81
(bd, 1 H, J 3.2 Hz, H-1), 4.46 (dd, 1 H, J 3.1, 10.5 Hz,
H-6a), 3.99 (dd, 1 H, J 1.9, 10.4 Hz, H-6b), 1.12 (d, 3
Compound 41a: colorless crystals, mp 87–88 °C; [h]D
+139.6° (c 0.2, CH2Cl2); IR (film): wmax 1762 cm−1
1
(CꢀO); H NMR (CDCl3): l 5.01 (d, 1 H, J 3.3 Hz,
H,
J
7.5 Hz, CH3); ESIHRMS: Calcd for
H-5a), 4.76 (d, 1 H, J 3.2 Hz, H-2), 3.98 (dd, 1 H, J 6.0,
12.8 Hz, H-8), 3.69, 3.43 (2 dq, 2 H, Et), 3.63 (dt, 1 H,
J 6.0, 9.3, 10.0 Hz, H-8a), 3.33 (ddd, 1 H, J 4.7, 9.3,
10.6 Hz, H-4a), 3.13 (ddd, 1 H, J 1.7, 3.3, 15.0 Hz,
H-6), 2.83 (dd, 1 H, J 0.5, 15.0 Hz, H-6%), 2.77 (ddd, 1
H, J 1.7, 10.2, 12.8 Hz, H-8%), 1.96–1.75 (m, 4 H,
H-3,3%,4,4%), 1.22 (t, 3 H, Et); ESIHRMS: Calcd for
C11H17NNaO4: 250.1050; found: m/z 250.1089 [M+
Na]+.
C19H27NNaO7S: 436.1420; found: m/z 436.1408 [M+
Na]+.
Ethyl 2,3-dideoxy-6-O-mesyl-4-O-(3%S,4%R)- and
(3%R,4%S)-(3%-methylazetidin-2%-on-4%-yl)-6-h-D-erythro-
hexopyranoside (36) and (39).—A mixture 36 and 39 in
a ratio of 1.6:1, respectively, was obtained by addition
of CSI to 30 following procedure described for 33
(42%).
Spectral data taken for the mixture 36 and 39: IR
Compound 41b: colorless crystals, mp 135–137 °C;
1
(film): wmax 3274 (NH), 1768 cm−1 (CꢀO); 36: H NMR
[h]D +7.8° (c 0.3, CH2Cl2); IR (film): wmax 1762 cm−1

K. Borsuk et al. / Carbohydrate Research 337 (2002) 2005–2015
2013
1
(CꢀO); H NMR (CDCl3): l 5.01 (d, 1 H, J 3.3 Hz,
Hz, H-3%), 0.86 (d, 3 H, J 7.5 Hz, CH3). LSIHRMS
taken for the mixture: Calcd for C44H45NNaO7:
722.3094; found: m/z 722.3143 [M+Na]+.
H-5a), 4.51 (dd, 1 H, J 2.2, 9.0 Hz, H-2), 4.06 (dd, 1 H,
J 5.7, 13.0 Hz, H-8), 3.90, 3.53 (2 dq, 2 H, Et), 3.29 (dt,
1 H, J 5.05, 9.1, 9.1 Hz, H-4a), 3.26 (dt, 1 H, J 5.7, 9.1,
9.5 Hz, H-8a), 3.14 (ddd, 1 H, J 1.7, 3.3, 15.0 Hz, H-6),
2.87 (ddd, 1 H, J 1.7, 9.5, 13.0 Hz, H-8%), 2.80 (dd, 1 H,
J 0.5, 15.0 Hz, H-6%), 2.10–1.55 (m, 4 H, H-3,3%,4,4%),
1.22 (t, 3 H, Et); ESIHRMS: Calcd for C11H17NNaO4:
250.1050; found: m/z 250.1076 [M+Na]+.
Methyl 2,3-di-O-benzyl-4-O-(3%R,4%S)- and (3%S,4%R)-
(3%-methylazetidin-2%-on-4%-yl)-h- -glucopyranosides (46)
D
and (47).—A mixture of compounds 44/45 was detrityl-
ated using 0.4% of p-TsOH in MeOH at room temper-
ature (yield 83%). Mixture 46/47 was used for the next
step without any purification.
(4aS,5aS,6R,8aR)
1,5-Dioxa-6-methyl-7a-aza-cy-
Methyl 2,3-di-O-benzyl-4-O-(3%R,4%S)- and (3%S,4%R)-
clobuta[b]decalin-2,7-one (42).—Compound 37 (0.05 g,
0.2 mmol) was dissolved in 50% aq dioxane, and p-
TsOH (0.002 g) was added. This mixture was heated
under reflux for 2.5 h, then extracted with EtOAc (3×5
mL) and dried over anhyd MgSO4, and the solvent was
evaporated to give syrup. This residue was dissolved in
water (5 mL), bromine (0.05 mL) and calcium carbon-
ate powder (0.1 g) were added, and the mixture was
stirred for 0.5 h. The excess of bromine was removed
with sodium bisulfite, and the product was extracted
with CH2Cl2. The extract was dried over anhyd MgSO4,
and the solvent was evaporated. The residue was
purified by column chromatography on silica gel using
2:3 hexane–EtOAc as the eluant to give 42 (0.02 g,
50%); oil; [h]D +7.6° (c 0.1, CH2Cl2); IR (film): wmax
(3%-methylazetidin-2%-on-4%-yl)-6-O-tosyl-h-D-gluco-
pyranosides (48) and (49).—A mixture 48/49 was ob-
tained according to the procedure described for 35
(70%). Colorless oil; spectral data taken for the mix-
1
ture; IR (film): wmax 1771 cm−1 (CꢀO); 48: H NMR
(CDCl3) selected signals: l 5.87 (bs, 1 H, NH), 5.06 (d,
1 H, J 4.6 Hz, H-4%), 4.2 (t, 1 H, J 9.2 Hz, H-3), 3.11 (s,
3 H, OCH3), 1.16 (d, 3 H, J 7.6 Hz, CH3); 49: 1H NMR
(CDCl3) selected signals: l 5.76 (bs, 1 H, NH), 4.66 (d,
1 H, J 4.1 Hz, H-4%), 4.3 (t, 1 H, J 9.3 Hz, H-3), 3.15 (s,
3 H, OCH3), 1.15 (d, 3 H, J 7.6 Hz, CH3); ESIHRMS:
Calcd for C32H37NNaO9S: 634.086; found: m/z 634.050
[M+Na]+.
(2S,3R,4S,4aR,5aS,6R,8aR) and (2S,3R,4S,4aR,
5aR,6S,8aR) 3,4-Dibenzyloxy-1,5-dioxa-2-methoxy-6-
1
3475 (NH), 1750 cm−1 (2×CꢀO); H NMR (CDCl3):
methyl-7a-aza-cyclobuta[b]decalin-7-one
(50)
and
l 5.03 (d, 1 H, J 3.7 Hz, H-5a), 4.24 (dd, 1 H, J 6.1,
13.2 Hz, H-8), 4.03 (dt, 1 H, J 6.1, 9.5, 9.8 Hz, H-8a),
3.67 (dt, 1 H, J 6.03, 9.5, 9.7 Hz, H-4a), 3.41 (ddq, 1 H,
J 1.6, 3.7, 7.6 Hz, H-6), 2.95 (ddd, 1 H, J 1.6, 9.8, 13.2
Hz, H-8%), 2.84 (ddd, 1 H, J 4.9, 8.8, 17.9 Hz, H-3), 2.67
(dt, 1 H, J 17.9, 8.1, 8.1 Hz, H-3%), 2.27 (m, 1 H, H-4),
1.96 (m, 1 H, H-4%), 1.22 (d, 3 H, J 7.6 Hz, CH3);
ESIHRMS: Calcd for C10H13NNaO4: 234.0737; found:
m/z 234.0722 [M+Na]+.
(51).—A mixture 50/51 was obtained from 48/49 ac-
cording to the procedure described earlier (60%). Com-
pounds 50 and 51 were separated on a silica gel column
using 60:35:5 toluene–CH2Cl2–acetone as the eluant.
Compound 50: Oil; [h]D +17.7° (c 0.3, CH2Cl2); IR
1
(film): wmax 1771 cm−1 (CꢀO); H NMR (C6D6): l 7.30,
7.05 (m, 10 H, Bn), 4.92, 4.79 (2 d, 2 H, J 11.5 Hz, Bn),
4.65 (d, 1 H, J 3.3 Hz, H-5a), 4.61, 4.42 (2 d, 2 H, J
12.0 Hz, Bn), 4.42 (d, 1 H, J 3.6 Hz, H-2), 4.02 (t, 1 H,
J 9.1 Hz, H-4), 3.68 (m, 2 H, H-8, H-8a), 3.52 (t, 1 H,
J 9.3 Hz, H-4a), 3.25 (dd, 1 H, J 3.6, 9.5 Hz, H-3), 3.05
(s, 3 H, OCH3), 2.95 (m, 1 H, H-8%), 2.78 (qdd, 1 H, J
1.7, 3.3, 7.6 Hz, H-6), 1.17 (d, 3 H, J 7.7 Hz, CH3);
ESIHRMS: Calcd for C25H29NNaO6: 462.1887; found:
m/z 462.1869 [M+Na]+.
Methyl 2,3-di-O-benzyl-4-O-(3%R,4%S)- and (3%S,4%R)-
(3%-methylazetidin-2%-on-4%-yl)-6-O-trityl-h-D-gluco-
pyranosides (44) and (45).—Cycloaddition of CSI to the
vinyl ether 17 was performed according to the proce-
dure described for 33. A mixture 44 and 45 in a ratio of
3:1, respectively, was obtained in 89% yield. Foam; IR
(film) taken for the mixture: wmax 3374, 3296 (NH), 1776
Compound 51: Oil; [h]D +18.9° (c 0.2, CH2Cl2); IR
1
1
cm−1 (CꢀO); H NMR (C6D6) taken for the mixture:
(film): wmax 1771 cm−1 (CꢀO); H NMR (C6D6): l 7.38,
44, l 5.20 (bd, 1 H, NH), 5.00 (d, 1 H, 4.5 Hz, H-4%),
4.79 (d, 1 H, J 3.4 Hz, H-1), 4.03 (t, 1 H, J 8.8, 9.5 Hz,
H-3), 3.88 (ddd, 1-H, J 1.6, 5.0, 10.0 Hz, H-5), 3.60 (dd,
1 H, J 3.4, 9.5 Hz, H-2), 3.52 (dd, 1 H, J 1.6, 10.0 Hz,
H-6), 3.47 (t, 1 H, J 8.8, 10.0 Hz, H-4), 3.29 (dd, 1 H,
J 5.0, 10.0 Hz, H-6%), 3.22 (s, 3 H, OCH3), 2.70 (qdd, 1
H, J 7.5, 2.6, 4.5 Hz, H-3%), 0.91 (d, 3 H, J 7.5 Hz,
CH3); 45: l 5.74 (bs, 1 H, NH), 4.78 (d, 1 H, J 3.4 Hz,
H-1), 4.47 (d, 3 H, J 4.5 Hz, H-4%), 4.03 (t, 1 H, J 8.5,
10.0 Hz, H-3), 3.80 (m, 1 H, H-5), 3.65 (dd, 1 H, J 3.4,
9.6 Hz, H-2), 3.62 (t, 1 H, J 8.5, 9.9 Hz, H-4), 3.45 (dd,
1 H, J 1.7, 10.0 Hz, H-6), 3.17 (s, 3 H, OCH3), 3.10 (dd,
1 H, J 3.8, 10.0 Hz, H-6%), 2.57 (qdd, 1 H, J 7.5, 1.3, 4.5
7.08 (m, 10 H, Bn), 4.87, 4.80 (2 d, 2 H, J 11.8 Hz, Bn),
4.61, 4.47 (2 d, 2 H, J 12.1 Hz, Bn), 4.48 (d, 1 H, J 3.5
Hz, H-2), 4.30 (d, 1 H, J 3.8 Hz, H-5a), 4.03 (t, 2 H, J
9.2 Hz, H-4), 3.99 (dd, 1 H, J 6.0, 12.7 Hz, H-8), 3.57
(ddd, 1 H, J 6.0, 9.3, 10.1 Hz, H-8a), 3.43 (dd, 1 H, J
3.6, 9.4 Hz, H-3), 3.09 (t, 1 H, J 9.3 Hz, H-4a), 2.90 (s,
3 H, OCH3), 2.82 (qdd, 1 H, J 1.5, 3.8, 7.4 Hz, H-6),
2.48 (ddd, 1 H, J 1.5, 10.1, 12.7 Hz, H-8), 1.06 (d, 3 H,
J 7.5 Hz, CH3); ESIHRMS: Calcd for C25H29NNaO6:
462.1887; found: m/z 462.1910 [M+Na]+.
(2S,3R,4S,4aR,6R,8aR) 3,4-Dibenzyloxy-1,5-dioxa-
2-methoxy-7a-aza-cyclobuta[b]-decalin-7-one (52).—
Compound 52 was obtained from mixture 32 following

2014
K. Borsuk et al. / Carbohydrate Research 337 (2002) 2005–2015
the procedure described for 41 (20%). Colorless oil; [h]D
+48.4° (c 0.2, CH2Cl2); IR (film): wmax 1772 cm−1
(CꢀO); H NMR (C6D6)): l 7.38–7.05 (m, 10 H, 2 Ph),
10 min at 37 °C. Next, to each sample was added 350
mL of 5:5:6 MeOH–distilled water–H2SO4. The extinc-
tion of the resulting solution was measured at 540 nm.
The inhibition of DD-peptidase 64-575 by the oxa-
cephams discussed above was evaluated.20 Mixtures of
10 mL of DD-peptidase 64-575 (40 U/mg), 5 mL solu-
tion of a cepham in MeOH and 5 mL of 0.1 M
phosphate buffer, pH 8.0 were incubated for 45 min at
37 °C. The concentration of a cepham in the mixture
was from 0.1 to 0.000055 M. After incubation 20 mL of
substrate solution was added to 20 mL of each sample,
and the resulting mixtures were incubated again. The
following oxacephams were tested: 7, 8, 9, 37, 40, 41a,
and 41b.
1
4.88, 4.81 (2 d, 2 H, J 11.5 Hz, Bn), 4.59, 4.45 (2 d, 2
H, J 12.1 Hz, Bn), 4.47 (d, 1 H, J 3.7 Hz, H-2), 4.3 (t,
1 H, J 2.2 Hz, H-5a), 4.0 (t, 1 H, J 9.4 Hz, H-4), 3.98
(dd, 1 H, J 6.0, 12.7 Hz, H-8), 3.57 (ddd, 1 H, J 6.0,
9.4, 9.8 Hz, H-8a), 3.41 (dd, 1 H, J 3.7, 9.4 Hz, H-3),
3.03 (t, 1 H, J 9.4 Hz, H-4a), 2.94 (s, 3 H, OCH3), 2.5
(m, 2 H, H-6,6%), 2.45 (dd, 1 H, J 9.8, 12.7 Hz, H-8);
ESIHRMS: Calcd for C24H27NNaO6: 448.1731; found:
m/z 448.1733 [M+Na]+.
(2S,3R,4S,4aR,6R,8aR) 3,4-Diacetoxy-1,5-dioxa-2-
methoxy-7a-aza-cyclobuta[b]-decalin-7-one (53).—To a
solution of 52 (0.05 g, 0.12 mmol) in MeOH (0.5 mL)
was added 5% Pd/C (0.005 g). (Caution! Extreme fire
hazard.) The mixture was stirred for 2 h under H2 at
room temperature. The catalyst was filtered through
Celite, and the filtrate was concentrated. The residue 53
was acetylated with Ac2O–pyridine, and the product
obtained after standard workup was purified by column
chromatography on silica gel using 2:3 hexane–EtOAc
as the eluant to afford 54 (0.025 g, 65%). Colorless
crystals; mp 149.3–150.5 °C; [h]D +83.8° (c 0.4,
CH2Cl2); IR (film): wmax 1773 cm−1 (CꢀO), 1750 cm−1
5. Supplementary material
Full crystallographic details, excluding structure fea-
tures for compound 41a, have been deposited (acces-
sion no. CCDC 184078) with the Cambridge
Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK (fax: +44-1223-336033; e-mail:
deposit@ccdc.cam.ac.uk or www: http://www.ccdc.
cam.ac.uk).
1
(Ac); H NMR (CDCl3): l 5.45 (t, 1 H, J 9.5, 10.0 Hz,
H-4), 4.99 (dd, 1 H, J 0.5, 3.3 Hz, H-5a), 4.88 (d, 1 H,
J 3.7 Hz, H-2), 4.84 (dd, 1 H, J 3.7, 10.0 Hz, H-3), 4.10
(dd, 1 H, J 6.0, 12.9 Hz, H-8), 3.72 (ddd, 1 H, J 6.0,
9.9, 9.9 Hz, H-8a), 3.40 (s, 3 H, OCH3), 3.39 (t, 1 H, J
9.5, 10.2 Hz, H-4a), 3.15 (ddd, 1 H, J 1.6, 3.3, 15.1 Hz,
H-6), 2.90 (dd, 1 H, J 0.5, 15.1 Hz, H-6%), 2.86 (ddd, 1
H, J 1.6, 10.2, 12.9 Hz, H-8%), 2.07 (2 s, 6 H, CH3);
ESIHRMS: Calcd for C14H19NNaO8: 352.1003; found:
m/z 352.0996 [M+Na]+.
Acknowledgements
This work was supported by the State Committee for
Scientific Research, Contract Grant Number T 09/
PBZ.6.04.
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