New and concise syntheses of the bicyclic oxamazin core using an intramolecular nitroso diels-alder reaction and ring-closing olefin metathesis

Article abstract of DOI:10.1021/ol303305u

Herein two new and concise synthetic approaches for making an unsaturated bicyclic oxamazin core are reported. The first involves the use of an intramolecular Diels-Alder reaction to form both of the fused rings in one step. The second approach incorporates ring-closing olefin metathesis in the final step to form the second fused ring of the core. The scope of the second approach was also expanded further to afford larger ringed bicyclic systems.

Full text of DOI:10.1021/ol303305u

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
New and Concise Syntheses of the
Bicyclic Oxamazin Core Using an
Intramolecular Nitroso DielsÀAlder
Reaction and Ring-Closing Olefin
Metathesis
Kyle D. Watson, Serena Carosso, and Marvin J. Miller*
Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland
Science Hall, Notre Dame, Indiana 46556, United States
*mmiller1@nd.edu
Received December 2, 2012
ABSTRACT
Herein two new and concise synthetic approaches for making an unsaturated bicyclic oxamazin core are reported. The first involves the use of an
intramolecular DielsÀAlder reaction to form both of the fused rings in one step. The second approach incorporates ring-closing olefin metathesis
in the final step to form the second fused ring of the core. The scope of the second approach was also expanded further to afford larger ringed
bicyclic systems.
β-Lactam antibiotics continue to play a fundamental
role in the treatment of infectious diseases caused by
bacteria.1 The discovery of penicillin 1 and cephalosporin
2 (Figure 1) inthe early half ofthe 20thcentury representsa
crucial point in the history of human health care and their
introduction into widespread use induced a dramatic im-
provement in the quality of life as well as a longer average
life expectancy.2 On the other hand, the era of β-lactam
antibiotics is also characterized by another important
phenomena: the rise of bacterial resistance.3 For example,
resistance to penicillin G was noted within one year after
its introduction into clinical use.4 Since then, numerous
efforts have been directed toward the discovery and devel-
opment of new molecules with improved antibacterial
activity either through isolation from natural sources or
synthetic methods. Nevertheless, the appearance of resis-
tant strains of bacteria is a growing concern and, since
the pipeline of available antibiotics has been diminished,
the development of new drugs is becoming more and more
urgent.
Oxamazins (3) are a class of monocyclic heteroatom
activated β-lactams that shows good biological activity
against Gram-negative bacteria.5 These compounds pos-
sess a unique structure since the ionizable group is one
atom further away from the β-lactam nitrogen compared
toothertraditional β-lactam antibiotics. Also, the presence
of the oxygen atom directly bonded to the nitrogen is
considered to be responsible for the electronic activation of
the azetidinone ring and, therefore, the biological activity
of these molecules.6
Our group and others have become interested in the
syntheses of bicyclic oxamazins 4 and 5 (Figure 1) since the
combination of the bicyclic structure and the heteroatom
€
(1) Durckheimer, W.; Blumbach, J.; Lattrell, R.; Scheunemann,
K. H. Angew. Chem., Int. Ed. 1985, 24, 180.
(2) Christensen, B. G. Chem. Br. 1989, 25, 371.
(3) Walsh, C. Nature 2000, 406, 775.
(5) Woulfe, S. R.; Miller, M. J. Tetrahedron Lett. 1984, 25, 3293.
(6) Cohen, N. C. J. Med. Chem. 1983, 26, 259.
(4) Walsh, C. Antibiotics: Actions, Origins, Resistance; ASM Press:
Washington, D.C., 2003.
r
10.1021/ol303305u
XXXX American Chemical Society

Scheme 2. Synthesis of Hydroxamic Acid 8
Figure 1. Representative heteroatom-activated β-lactams.
activation is envisaged to afford compounds with im-
proved antibiotic activity.7 Herein we report the synthesis
of the unsaturated bicyclic oxamazin core 6 in which
the double bond may constitute a handle for further
functionalization.
the β-lactam and the fused ring was obtained in a single
step. Encouraged by this result, we considered the use
of different oxidants and solvent systems for the oxidation
reaction (Table 1).
Two different synthetic approaches have been used: the
first involves an intramolecular nitroso DielsÀAlder reac-
tion as the key step while the second relies on a Mitsunobu
cyclization followed by ring-closing olefin metathesis.
We also report the application of the second methodology
to the syntheses of bicyclic structures with different ring
sizes and with an alkyl substituent on the double bond.
We at first envisaged that the core of bicyclic oxamazin 6
could be made in one step using an intramolecular
DielsÀAlder reaction of the transient nitrosocarbonyl
compound 7, which in turn could be generated through
the oxidation of hydroxamic acid 8 (Scheme 1).
Table 1. Nitroso Hetero DielsÀAlder Reaction
entry
oxidant
solvent
MeOH
yield (%)
1
2
3
4
5
nBu4NIO4
nBu4NIO4
PhI(OAc)2
PhI(OAc)2
nBu4NIO4
17
17
15
10
34
DCM/DMF
CHCl3
DMF
CHCl3/DMF
Although the best yield for compound 6 was obtained
using the reaction conditions shown in entry 5, it was not
routinely reproducible because of the inherent instability
and competitive reactivity of acylnitroso moieties.8 For
this reason, we decided to consider a different approach
in which the β-lactam ring and the fused ring would be
constructed in two different steps: a Mitsunobu reaction
followed by ring-closing metathesis.
Several publications have reported the syntheses of
strained ring systems through a ring-closing methatesis reac-
tion using either Grubbs’ first generation9 or second genera-
tion catalyst.10 This methodology has also been shown to be
effective in the formation of the second ring of sulfactam
derivatives11 as well as larger lactam ring systems12 and large
cyclic heteroatom-containing compounds.13
Scheme 1. Retrosynthetic Analysis of β-Lactam 6
Hydroxamic acid 8 was synthesized in three steps from
commercially available sorbic acid (Scheme 2). Thus, after
conversion of sorbic acid toits methyl ester 9, the diene was
deconjugated from the ester by treatment with LDA and
subsequent reprotonation at low temperature to afford
compound 10. Finally, treatment of the methyl ester of 10
with an excess of freshly prepared hydroxylamine in
methanol gave hydroxamic acid 8 in moderate yield.
With the preparation of compound 8 being completed,
we turned our attention to the key step of the synthesis: the
intramolecular nitroso DielsÀAlder reaction. The oxida-
tion of hydroxamic acid 8 was initially performed in
methanol at 0 °C using nBu4NIO4 as the oxidant. Bicyclic
β-lactam 6 was obtained in 17% yield. Although the yield
was low, this result was still notable since the formation of
(8) (a) Sparks, S. M.; Chow, C. P.; Zhu, L.; Shea, K. J. J. Org. Chem.
2004, 69, 3025. (b) Keck, G. E. Tetrahedron Lett. 1978, 19, 4767. (c)
Keck, G. E.; Webb, R. R.; Yates, J. B. Tetrahedron 1981, 37, 4007.
(9) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem, Int. Ed. 1995, 34, 2039. (b) Schwab, R.; Grubbs, R. H.; Ziller,
J. W. J. Am. Chem. Soc. 1996, 118, 110.
(10) (a) Barrett, A. G. M.; Baugh, S. P. D.; Braddock, C.; Flack, K.;
Gibson, V. C.; Giles, M. R.; Marshall, E. L.; Procopiou, P. A.; White,
A. J. P.; Williams, D. J. J. Org. Chem. 1998, 63, 7893. (b) Alcaide, B.;
Almendros, P.; Alonso, J. M.; Redondo, M. C. J. Org. Chem. 2003, 68,
1426.
(11) Frietag, D.; Schwab, P.; Metz, P. Tetrahedron Lett. 2004, 45,
3589.
(12) Lennartz, M.; Steckhan, E. Synlett 2000, 3, 319.
(13) Yang, Y.-K.; Tae, J. Synlett 2003, 7, 1043.
(7) (a) Kronethal, D.; Kuester, P.; Koster, W. H. Abstracts from the
Tenth International Congress of Heterocyclic Chemistry, Abstract
G3À25, 1985. (b) Ghosh, M.; Miller, M. J. Tetrahedron 1996, 52, 4225.
(c) Zercher, C. K.; Miller, M. J. Tetrahedron Lett. 1989, 30, 7009.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Revised Route for the Synthesis of β-Lactam 6
Scheme 4. Syntheses of Bicyclic β-Lactams 6aÀc
Our revised approach for the synthesis of the bicyclic
oxamazin core 6 (n = 1) is displayed in Scheme 3 and
involves a ring-closing metathesis reaction as the final step.
We anticipated that the cyclization precursor 11 would be
obtained from the corresponding hydroxamate 12 using
methodology developed in our group.14 We planned to
prepare linear hydroxamate 12 by our standard water-
soluble carbodiimide-mediated coupling of Reformatsky-
derived carboxylic acid 13 with allyl protected hydroxyla-
mine 14 (n = 1). It is worth noting the wider scope of this
methodology since the use of a protected hydroxylamine
with a longer alkyl chain (n > 1) would allow the synthesis
of β-lactams fused with larger ring systems.
Table 2. Ring-closing Metathesis on Precursors 11aÀc
To initiate the syntheses, hydroxylamines 14aÀc
(Scheme 4) were prepared starting from hydroxylamine
hydrochloride by Boc protection followed by O-alkylation
and subsequent acidic removal of the Boc protecting group
to give the corresponding hydrochloride salts. Carboxylic
acid 13 was obtained in two steps: a Reformatsky reaction
between acrolein 15 and ethyl bromoacetate 16, which
afforded ethyl ester 18 in moderate yield, followed by
saponification to the carboxylic acid.
Standard coupling between carboxylic acid 13 and
amines 14aÀc under aqueous conditions afforded com-
pounds 12aÀc, which were cyclized under Mitsunobu
conditions14c,15 to afford β-lactams 11aÀc. It should be
noted that no δ-lactams were observed from allylic reac-
tions during the Mitsunobu process.
Formation of the targeted bicyclic β-lactams 6aÀc using
Grubbs’ second generation catalyst9 for ring-closing me-
tathesis was then studied and yields were found to depend
on ring size (Table 2). It should be noted that attempted
metathesis reactions involving Grubbs’ first generation
catalyst gave no product formation.
Encouraged by these results, we considered subtle struc-
tural modifications to further expand the scope of this
methodology. The replacement of acrolein with an appro-
priate unsaturated aldehyde was envisaged to allow the
syntheses of bicyclic structures containing a trisubstituted
double bond (Scheme 5). Thus, we opted to first incorporate
a methyl group into the bicyclic system. While this might
seem to be a simple change, it should be pointed out that
similar incorporation of a methyl substituent in carbapenems
had a dramatic impact in antibiotic development. Appro-
priately, placement of a β-methyl group in imipenem analogs
improved their efficacy and circumvented their susceptibil-
ity to human renal peptidases.16 Thus, use of methacrolein
19 in the Reformatsky reaction, followed by saponification,
gave carboxylic acid 21. Coupling of 21 with amines 14aÀc
afforded the late intermediates 22aÀc, which underwent
cyclization under Mitsunobu conditions to give β-lactams
23aÀc. The ring-closing metathesis step was then again
attempted using the Grubbs’ second generation catalyst
(Table 3).
As shown in Table 3, the attempted cyclization of
compound 23a to afford the [4.2.0] bicyclic system 24a,
the methyl substituted analog of 6a, proved to be proble-
matic since only starting material was reisolated under
different reaction conditions. This could be a result of the
inherent strain of the intermediate. On the other hand,
(14) (a) Miller, M. J.; Mattingly, P. G.; Morrison, M. A.; Kerwin,
J. F., Jr. J. Am. Chem. Soc. 1980, 102, 7026. (b) Miller, M. J.; Mattingly,
P. G. Tetrahedron 1983, 39, 2563. (c) Miller, M. J. J. Acc. Chem. Res.
1986, 19, 49.
(16) Humphrey, G. R.; Miller, R. A.; Pye, P. J.; Rossen, K.; Reamer,
R. A.; Miliakal, A.; Ceglia, S. S.; Grabowski, E. J. J.; Volante, R. P;
Reider, P. J. J. Am. Chem. Soc. 1999, 121, 11261.
(15) Mitsunobu, O. Synthesis 1981, 1.
Org. Lett., Vol. XX, No. XX, XXXX
C

the standard peripheral substituents needed for recogni-
tion by antibiotic targeted enzymes, we screened them
against a panel of Gram-negative and Gram-positive
bacteria via agar-diffusion assays. Not surprisingly, none
of the compounds were active. However, with the metho-
dology in hand for formation of the key bicyclic oxamazins,
further studies are focused on preparation of precursors
with appropriate recognition elements, including pendant
acylamino and ionizable groups.
Scheme 5. Syntheses of Bicyclic β-Lactams 24aÀc
Herein we have reported the synthesis of the bicyclic
oxamazin core 6 using two different synthetic approaches.
The first involved an intramolecular nitroso DielsÀAlder
reaction as the key step and afforded the desired com-
pound 6a, despite the inherent competitive reactivity of the
acylnitroso moiety. The second strategy involved the for-
mation of the β-lactam ring under Mitsunobu conditions
followed by the formation of the second ring using a ring-
closing metathesis reaction. We also demonstrated that the
second strategy could be used for the construction of larger
[5.2.0] and [6.2.0] ring systems and as well as the introduc-
tion of an alkyl substituent on the double bond. Since all
the β-lactams synthesized did not have biological activity,
further work will be focused on the functionalization of
bicyclic systems 6aÀc and 24aÀc.
Table 3. Ring-closing Metathesis on Compounds 23aÀc
Acknowledgment. We gratefully acknowledge Patricia
Miller (UND) for biological data, Nonka Sevova and
Dr. Bill Bogges (Mass Spectrometry and Proteomics Fa-
cility, UND) for mass spectroscopic analyses, Dr. Jaroslav
Zajicek (Lizzadro Magnetic Resonance Research Center,
UND) for NMR assistance, and Ms. Kathleen Peterson
(UND) for use of IR instrumentation. We acknowledge the
University of Notre Dame, Rempex Pharmaceuticals, Inc.,
and NIH (1R21 AI098689) for support of this work. K.D.W.
acknowledges a Grace Fellowship (2011-2012, UND).
a Only monocyclic β-lactam starting material was recovered.
under the same conditions, the larger bicyclic systems
24b (n = 2) and 24c (n = 3) were obtained in moderate
yield from the cyclization of compounds 23b and 23c,
respectively.
Supporting Information Available. Experimental pro-
cedures and characterization spectral data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
Although monocyclic β-lactams 11aÀc and 23aÀc and
the corresponding bicyclic systems 6aÀc and 24aÀc lack
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX