Scheme 3a
Scheme 4a
a Reagents and conditions: (a) NH2OH‚HCl/NaOAc/EtOH/H2O
(90%); (b) NCS/DMF (83%); (c) (Bu3Sn)2O/benzene.
11. In contrast, bis(tributyltin)oxide, a neutral reagent,13 was
found to be a superior reagent for dehydrochlorination, giving
better yields of cycloadducts in almost all cases. For example,
when methyl propiolate was used as the trapping agent, the
corresponding cycloadduct was obtained in 56% yield with
bis(tributyltin)oxide as opposed to 20% yield with Et3N.
Thus, the treatment of nitrile oxide 11 with a series of
alkenes and alkynes gave the corresponding dipolar cycload-
ducts in moderate to good yields regardless of their electronic
nature.14 Reaction of 11 with methyl acrylate gave the
isoxazoline cycloadducts in 50% yield as a 1:1 mixture of
diastereoisomers 12a and 13a. As expected, no regioisomers
were formed. A similar reactivity pattern was observed with
phenyl vinyl sulfone to give the diastereoisomeric cycload-
ducts 14a and 15a in 52% yield. The cycloaddition proceeded
smoothly with electron-rich dipolarophiles such as phenyl
vinyl sulfide and tert-butyl vinyl ether, giving the corre-
sponding cycloadducts in 60% and 68% yields, respectively.
In both cases, mixtures of diastereoisomers at the 5-position
of the isoxazoline ring were obtained with complete regio-
selectivity. Styrene also participated well in this process,
giving the cycloaddition products in 54% yield as a 1:1
mixture of diastereoisomers, 20a and 21a (Scheme 4).
Although the alkenes used in this process gave 5-substi-
tuted isoxazoline penam sulfones with complete regioselec-
tivity, certain alkynes gave both 5- and 4-substituted
isoxazole derivatives. The cycloaddition reaction between
methyl propiolate and the dipole 11 gave a 6:1 mixture of
regioisomeric products in 56% yield. In this case, 5-isoxazole
isomer 22a was the major one. In contrast, when p-tolyl
ethynyl sulfone was used as the trapping agent, the major
isomer obtained was the 4-isoxazole substituted penam
sulfone 26a in a 2:1 ratio. The assigned regiochemistry of
the products follows from their 1H NMR spectra. The relative
positions of the isoxazole ring hydrogens of the regioisomeric
products 25a and 26a are well separated with an ∼2 ppm
chemical shift value. A similar reaction with N′-propynoyl-
a Series a: R ) CHPh2 (esters).
hydrazinecarboxylic acid tert-butyl ester15 reagent gave a 1:1
mixture of regioisomers 27a and 28a. Methyl and phenyl
propargyl ketones as well as TMS-acetylene gave exclu-
sively 5-substituted products 30a, 29a, and 24a, respectively,
in good yields. The reaction proceeded smoothly with
disubstituted alkyne, DMAD, giving the cycloaddition
product 31a in 52% yield. The regiochemical outcomes
observed in these examples can be rationalized by FMO
considerations.16 Depending on the size of the coefficients,
a favorable HOMO-LUMO interaction between the dipole
and the dipolarophile leads to the observed regioselectivity.
In general, dipole (LUMO)-dipolarophile (HOMO) interac-
tion seems to be dominant for alkenes whereas both dipole
(HOMO) and dipole (LUMO) become important for alkynes
depending upon the nature of the substituent. This is apparent
from the dramatic selectivity difference between methyl
propiolate and p-tolyl ethynyl sulfone.
The acid derivatives of some of these compounds were
evaluated for their inhibitory activity against three repre-
sentative â-lactamase enzymes from different enzyme classes
(Table 1).17 First, the benzhydryl esters were converted to
the corresponding acids (series b: R ) H) by catalytic
hydrogenolysis (H2, Pd-C, EtOAc). The inhibitory activity
of the acids were compared with the reference compounds,
sulbactam and tazobactam. Our objective was a compound
with a sub-micromolar IC50 against at least class A and class
C enzymes, which are the most common â-lactamase
enzymes found in bacteria. Table 1 presents the IC50 data
(15) Coppola, G. M.; Damon, R. E. Synth. Commun. 1993, 23(14), 2003.
(16) (a) Houk, K. N.; Sims, J.; Duke, R. E.; Strozier, R. W.; George, J.
K. J. Am. Chem. Soc. 1973, 95, 7287. (b) Sustmann, R.; Trill, H. Angew.
Chem., Int. Ed. Engl. 1972, 11, 838.
(17) For details about the assay and experimental procedure, see: Bush,
K.; Macalintal, C.; Rasmussen, B. A.; Lee, V. J.; Yang, Y. Antimicrob.
Agents Chemother. 1993, 37, 851.
(13) Moriya, O.; Urata, Y.; Endo, T. J. Chem. Soc., Chem. Commun.
1991, 17.
(14) All new compounds were fully characterized (NMR, IR, HRMS/
MS). These data are included in the Supporting Information.
Org. Lett., Vol. 2, No. 20, 2000
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