Diastereoselective synthesis of a hydroxamate containing bicyclo-[3.2.0] β-lactam aminal via ruthenium alkene isomerization and Pd(II)-catalyzed oxidative amidation

Article abstract of DOI:10.1016/j.tetlet.2014.12.072

With antibiotic resistance on the rise, the need for new medicinal scaffolds is needed. The synthesis of an aminal bicyclic β-lactam core is described. The key synthetic step is Pd(II)-catalyzed oxidative amidation. The product is a single diastereomer, c

Full text of DOI:10.1016/j.tetlet.2014.12.072

Accepted Manuscript
Diastereoselective synthesis of a hydroxamate containing bicyclo-[3.2.0] β-lac-
tam aminal via ruthenium alkene isomerization and Pd(II)-catalyzed oxidative
amidation
Maria O. Jobbins, Mark W. Majewski, Allen G. Oliver, Marvin J. Miller
PII:
S0040-4039(14)02138-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.12.072
TETL 45596
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 November 2014
11 December 2014
12 December 2014
Please cite this article as: Jobbins, M.O., Majewski, M.W., Oliver, A.G., Miller, M.J., Diastereoselective synthesis
of a hydroxamate containing bicyclo-[3.2.0] β-lactam aminal via ruthenium alkene isomerization and Pd(II)-
catalyzed oxidative amidation, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.12.072
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Diastereoselective synthesis of a
hydroxamate containing bicyclo-[3.2.0] β-
lactam aminal via ruthenium alkene
isomerization and Pd(II)-catalyzed oxidative
amidation
Maria O. Jobbins, Mark W. Majewski, Allen G. Oliver, and Marvin J. Miller*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Diastereoselective synthesis of a hydroxamate containing bicyclo-[3.2.0] β-lactam
aminal via ruthenium alkene isomerization and Pd(II)-catalyzed oxidative amidation
Maria O. Jobbins, Mark W. Majewski, Allen G. Oliver, and Marvin J. Miller*
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, USA
Telephone: 574 631 7571
Fax: 574 631 6652
Email: mmiller1@nd.edu
ARTICLE INFO
ABSTRACT
Article history:
Received
With antibiotic resistance on the rise, the need for new medicinal scaffolds is needed. The
synthesis of an aminal bicyclic β-lactam core is described. The key synthetic step is Pd(II)-
catalyzed oxidative amidation. The product is a single diastereomer, confirmed by x-ray
crystallography.
Received in revised form
Accepted
Available online
2014 Elsevier Ltd. All rights reserved.
Keywords:
β-Lactam, bicyclic β-Lactam, hydroxamate, ring
closure, aminal oxidative amidation
1. Introduction
Figure 1. Previously Reported Cores and Proposed Core.
The β-lactam family continues to be a mainstay in the never
ending microbial war. Despite being discovered over 80 years
ago, this class of antibiotics has almost single-handedly
substantially increased life expectancy. First starting out with the
classic penam (penicillin) core, this family has undergone
significant evolution in response to bacterial resistance. Bacteria
have a multitude of mechanisms which render β-lactams inactive,
such as porin depletion and β-lactamases which inactivate β-
lactams via hydrolysis.1 Thus there is dire need to both innovate
and improve upon the current β-lactam medicinal arsenal. Herein
we report the synthesis of a bicyclic aminal β-lactam core
featuring hydroxamate functionality.
The aminal, or N,N-acetal3 functional group has been
previously incorporated into bicyclic β-lactams.4-5 As a ready
example, Branch and Pearson utilized a 1,3-dipolar cycloaddition
which underwent thermolysis to access amide-containing
bicyclic-[3.2.0] and [4.2.0] β-lactams. Additionally, there have
been reports of transition metal catalyzed amidations to give
aminal cores of varying sizes. Grigg synthesized aminals
through Pd(0)-catalyzed cyclization of allenes with aryl iodides,
followed by attack of an amine on the resulting π-allyl complex.
(Scheme 1).6-7 Balazs demonstrated that aminal heterocycles of
varying size could be obtained when tosyl protected cis and trans
N-allyl-2-aminocyclohexanecarboxamides were subjected to
We have become interested in the incorporation of
hydroxamates and hydroxamic acids into bicyclic β-lactam
scaffolds.
Recently, we reported on the syntheses of
hydroxamate and hydroxamic acid containing bicyclic β-lactams
via palladium-catalyzed oxidative amidation of alkenes.2 With
this work in mind, we were interested to see if the methodology
could be extended to other bicyclic hydroxamate containing β-
lactam cores. Of particular interest was the aminal core, one in
which the hydroxamate functionality has been moved around the
ring (Figure 1).
specific
Pd(II)-
catalyzed
intramolecular oxidative conditions.8
Scheme 1. Sample Precedented Cyclizations to Afford Aminals.

2
Tetrahedron
2. Synthesis and Discussion
While we were pleased that the β-lactam-containing aminal
core could be made, low yields during the cyclization process
reinforced our initial concerns about the inherent stability of this
unique system. Indeed, while studying this reaction, we noticed
a persistent by-product. Based on our preliminary data, we
hypothesized that 5 may engage in a competitive elimination to
give benzaldehyde. To further substantiate this notion we
performed a benzaldehyde trapping experiment. During the
reaction for conversion of 4 to 5, an aliquot was removed and
added to a stirring solution of phenylhydrazine. LC/MS analysis
of this reaction mixture confirmed the formation of the
phenylhydrazone from reaction with released benzaldehyde.
With this data, a plausible mechanism is proposed in Figure 2.
Thus, as expected, the bicyclo-[3.2.0] β-lactam aminal is
inherently more reactive than our previously reported
hydroxamate-containing bicycle-[4.2.0] β-lactam, not only
While our earlier studies2 provided methodology for direct
incorporation of a hydroxamate into a bicyclic β-lactam and the
precedents noted above indicated that cyclic aminals can be
formed using Pd-mediated chemistry, generation of a highly
strained bicyclic aminal with one nitrogen as part of a β-lactam
and the other a hydroxamate was anticipated to be a significant
test of the methodology and inherent stability of the potential
product. With these concerns in mind, we decided to first test the
ability to form the novel bicyclic β-lactam aminal core. Our
successful synthesis of the aminal bicyclic core is shown in
Scheme 2. First N-Boc-O-benzylhydroxylamine was alkylated
with allylbromide followed by treatment with TFA and
concentrated HCl to give N-allyl-O-benzylhydroxylamine
because
of
ring strain but the new product also
incorporates
the more
reactive aminal.
Scheme 2. Synthesis of Bicyclo-[3.2.0] β-lactam Aminal.
O
O
H
hydrochloride9 1 in good yield. This hydroxylamine was then
coupled to 4-carboxy β-lactam 210 with EDC•HCl and HOBt to
O
N
N
O
Decomposition
give β-lactam hydroxamate 3.
conditions were then screened (Table 1). Among the catalysts
Alkene isomerization11-12
H
13-14
X
screened, RuHCOCl(PPh3)3
with careful NMR monitoring resulted in an optimized 75% yield
(0.09 equiv.) in refluxing THF
Figure 2. Proposed Mechanism for the Formation of
Benzaldehyde.
of 4. With 4 in hand, we then tested conditions for cyclization to
aminal 5.
Aza-Wacker cyclization conditions (Pd(OAc)2,
Lastly, the stereochemistry of 5 was confirmed with X-ray
crystallography. We were delighted to see that only the trans
diastereomer was formed, corresponding to the configuration
normally associated with classic β-lactam scaffolds that are
active antibiotics.15
pyridine, and O2) resulted in the decomposition of 4. However
Pd(II)-catalyzed oxidative amidation conditions (Pd(OAc)2, 1,4-
benzoquinone, and AcOH) in freshly distilled MeCN at 50˚C for
22 h gave 5 with an initial yield of 18%. The yield was slightly
enhanced by changing both the Pd loading and reaction time
(Scheme 2).
Table 1. Conditions Employed for Alkene Isomerization .
Catalyst,
Solvent
EtOH
MeOH
THF
Conditions
40˚C, 23 h
60˚C, 20 h
60˚C, 4 h
Results
No Rxn
No Rxn
Additive(s)
RhCl(PPh3)3
DBU, Sieves
Grubbs 2nd
Generation
RuHCOCl(PPh3)3
(0.03 eq)
Mixture of
3&4
RuHCOCl(PPh3)3
(0.03 eq)
THF
60˚C, 28 h
50-60˚C, 3 h
Decomposition
Figure 3. X-ray Structure for Bicyclo-[3.2.0] β-Lactam Aminal
4.
RuHCOCl(PPh3)3
(0.09 eq)
THF
4, 71 %

3
To close, we have developed diastereoselective methodology
for the synthesis of a hydroxamate containing bicyclo-[3.2.0] β-
lactam aminal. Future work includes both the extension of our
methodology to synthesize other hydroxamate-containing β-
lactam cores and the incorporation of peripheral
functionalization.
Acknowledgments
M.O.D. thanks Eli Lilly for supporting this research through a
graduate fellowship. M.W.M acknowledges an ECK Institute
Global Health Fellowship. We also gratefully acknowledge
Nonka Sevova and Dr. Bill Boggess (Mass Spectrometry and
Proteomics Facility, UND) for mass spectroscopic analyses.
We also are pleased to dedicate this manuscript to the memory of
Professor Harry H. Wasserman. Not only was Harry an
enthusiastic supporter of organic chemistry, including beta-
lactam chemistry, but his service as long-time editor of
Tetrahedron Letters, had a positive impact on many of us and our
profession.
References and notes
1. Llarrull, L. I.; Testero, S.A.; Fisher, J.F.; Mobashery, S. Curr.
Opin. Microbiol. 2010, 13, 551-557.
2. Jobbins, M.O.; Miller, M.J. J. Org. Chem. 2014, 79, 1620-1625.
3. Hiersemann, M.; Katritzky, A. R.; Taylor, R. J. K. Functions
Bearing Two Nitrogens; Elsevier: Amsterdam, 2005; Vol. 4, pp.
411-441.
4. Brown, D.; Brown, G.; Andrews, M.; Large, J.; Urban, D.; Butts,
C.; Hales, N.; Gallagher, T. J. Chem. Soc. Perkin Trans. 1 2002,
2014-2021.
5. Branch, C.; Pearson, M. J, Chem.. Soc. Perkin Trans. 1 1986,
1077-1095.
6. Grigg, R.; Sridharan, V.; Xu, L. J. Chem. Soc. Chem. Comm.
1995, 1903-1904.
7. Grigg, R.; Koppen, I.; Rasparini, M.; Sridharan, V. Chem. Comm.
2001, 964-965.
8. Balazs, A.; Hetenyi, A.; Szakonyi, Z.; Sillanpaa, R.; Fulop, F.
Chem. Eur. J. 2009, 15, 7376-7381.
9. Sulsky, R.; Demers, J. Tetrahedron Lett. 1989, 30, 31-34.
10. Baldwin, J.; Adlington, R.; Gollins, D.; Schofield, C. Tetrahedron
1990, 46, 4733-4748.
11. Krompiec, S.; Krompiec, M.; Penczek, R.; Ignasiak, H. Coord.
Chem. Rev. 2008, 252, 1819-1841.
12. Donohoe, T. J.; O'Riordan, T. J. C.; Rosa, C. P. Angew. Chem.,
Int. Ed. 2009, 48, 1014-1017.
13. Krompiec, S.; Pigulla, M.; Krompiec, M.; Baj, S.; Mrowiec-
Bialon, J.; Kasperezyk, J. Tetrahedron Lett. 2004, 45, 5257-5261.
14. Toumi, M.; Couty, F.; Evano, G. J. Org. Chem. 2008, 73, 1270-
1281.
15. Page, M.I. Acc. Chem. Res. 1984, 17, 144-151.

Highlights:
•
•
•
Emerging resistance to antibiotics requires development of new antibiotic
scaffolds
Methodology is described for synthesis of a new bicyclic beta-lactam core
structure
Oxidative amidation of a monocyclic beta-lactam produces a new bicyclic
core