Syntheses of hydroxamic acid-containing bicyclic β-lactams via palladium-catalyzed oxidative amidation of alkenes

Article abstract of DOI:10.1021/jo402544p

Palladium-catalyzed oxidative amidation has been used to synthesize hydroxamic acid-containing bicyclic β-lactam cores. Oxidative cleavage of the pendant alkene provides access to the carboxylic acid in one step.

Full text of DOI:10.1021/jo402544p

Article
pubs.acs.org/joc
Syntheses of Hydroxamic Acid-Containing Bicyclic β‑Lactams via
Palladium-Catalyzed Oxidative Amidation of Alkenes
Maria O. Jobbins and Marvin J. Miller*
Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, Indiana 46556,
United States
S
* Supporting Information
ABSTRACT: Palladium-catalyzed oxidative amidation has been used to synthesize hydroxamic acid-containing bicyclic β-lactam
cores. Oxidative cleavage of the pendant alkene provides access to the carboxylic acid in one step.
interest in developing both bicyclic and monocyclic β-lactams
with iron-chelating moieties4−6 (Figure 2). These compounds
have increased potency that is hypothesized to be due to active
transport by the cell’s iron uptake pathways.
INTRODUCTION
■
Human life expectancy increased dramatically with the advent
of antibiotics.1 However, because of the extensive use (and
often overuse) of antibiotics as well as an innovation gap in
antibiotic research, common infections are once again
becoming deadly.2 There is a great need for continued research
in antibiotics.3 β-Lactam antibiotics have been on the market
since penicillin was introduced in the 1940s. This class of
antibiotics has been kept viable by extensive structure−activity
relationship (SAR) studies on the side chains and, to a lesser
extent, on the bicyclic core (Figure 1).
The penicillin and cephalosporin cores can be obtained
through biosyntheses and semisyntheses. However, access to
the carbapenem core is less biosynthetically amenable.
Therefore, significant effort has focused on the development
of effective syntheses of this highly strained bicyclic core. Durst
investigated various approaches to electrophilically activate
alkenes and found that I2 and Hg(OAc)2 worked reasonably
well on unfunctionalized systems7 such as 2 to give 3 (Scheme
1). Kametani utilized an electrophilic cyclization approach with
pendant alkenes and phenylsulfenyl chloride to give the
carbapenem scaffold 4 in fair yield. However, this approach
gave low yields for more highly functionalized systems.8
Johnson further elaborated on Durst’s results and showed
that I2 and propylene oxide gave a reproducible though modest
yield of 5.9
Gram-negative pathogens are especially resistant to β-lactam
antibiotics and β-lactamase inhibitors, as their arsenal of
resistance mechanisms includes a highly impermeable cell
wall. In order to overcome this barrier, there has been an
Transition-metal-catalyzed methods have also been em-
ployed. Kozawa and Mori10 showed that propargyl carbonates,
when treated with Pd(0), give the unsaturated bicyclic β-lactam
system 7 (Scheme 2). They also showed that vinylic halides can
be cyclized onto the lactam nitrogen with Pd(0).11 Later, Xu
demonstrated that Cu(I)-catalyzed couplings with vinylic
halides can be used to access highly functionalized carbapenems
10.12 Additionally, cyclization with pendant allenes has been
observed by Liebeskind with Pd(II),13 Hiemstra with Pd(0),14
and Seomoon with Au(III)15 (Scheme 3).
Palladium-catalyzed oxidative amidation of alkenes has
developed into a general way to make nitrogen-containing
heterocycles, with the best results being obtained from
intramolecular cyclizations and less basic (i.e., acylated or
Received: November 17, 2013
Figure 1. Penicillin G and representative antibiotic core structures.
© XXXX American Chemical Society
A
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Figure 2. β-Lactam antibiotics with iron-binding functionality.
Scheme 1. Precedented Electrophilic Cyclizations onto the
Scheme 3. Precedented Cyclizations with Allenes
β-Lactam Nitrogen
Scheme 2. Transition-Metal-Catalyzed Cyclizations
transport or a handle for further functionalization, such as the
addition of iron-chelating side chains. To access this core, we
hypothesized that pendant alkenes could provide appropriate
substrates for palladium-catalyzed oxidative amidation. The
resulting core would contain an alkene that could be further
functionalized to give the ionizable carboxylic acid moiety
(Figure 3).
Figure 3. Partial retrosynthetic plan for the generation of hydroxamic
acid-containing bicyclic β-lactams.
RESULTS AND DISCUSSION
■
tosylated) nitrogens.16 The transformation involves Pd(II)-
catalyzed aminopalladation of the alkene to form the C−N
bond and, upon β-hydride elimination, generation of an alkene
and Pd(0). Pd(II) is then regenerated with an oxidant such as
O2/DMSO, O2/pyridine, Cu(II)/O2, or benzoquinone (BQ).17
Although decades of extensive studies were focused on
modification of peripheral substituents and the core compo-
nents of β-lactams in efforts to generate new antibiotics,
modern methodologies could facilitate the generation of new
variants that might provide opportunities for overcoming
continuously evolving resistance problems. Here we report on
our interest in expanding the known SAR of bicyclic β-lactams
by including a hydroxamic acid moiety directly into the fused
ring. This could provide a point for iron-chelate-mediated
As shown in Scheme 4, the construction of functionalized
monocyclic β-lactams 17a and 17b, which was necessary for
testing the metal-mediated formation of the targeted bicyclic β-
lactams, required the preparation of two key components: an
appropriately functionalized hydroxylamine 20 and 4-carboxy-
2-azetidinone (23). Thus, N-Boc-O-benzylhydroxylamine was
alkylated with allyl bromide and crotyl bromide to give 19a and
19b, respectively, in excellent yields. The products were
deprotected with TFA, and the free hydroxylamines were
treated with conc. HCl to give salts 20a and 20b.18,19 β-Lactam
carboxylic acid 23 was synthesized from L-aspartic acid in four
steps using literature precedent.20 The β-lactam and hydroxyl-
amines were then coupled using EDC·HCl to give 17a and
17b.
B
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Scheme 4. Syntheses of (S)-4-N-[Allyl/Crotyl]-N-(benzyloxy)carboxamide β-Lactams 17a/17b
With pendant alkene-containing β-lactam 17a in hand, we
investigated cyclization conditions. We found that aza-Wacker
cyclization conditions21 gave the desired bicycle 24 in fair yield
(eq 1). Attempts to optimize this reaction revealed that MeCN
increasing the loadings of BQ and AcOH to 150 and 160 mol
%, respectively, gave 16 in 60% yield. The configuration shown
in the structure of 16 was assigned by ROESY NMR.
Formation of this single diastereomer was very exciting since
it was anticipated that eventual conversion to carboxylic acid 25
would then give the relative and absolute configuration at the
two stereogenic centers most often associated with biological
activity of bicyclic β-lactams.
Oxidation of the pendent alkene 16 to the desired carboxylic
acid 25 was achieved by ozonolysis followed by a Pinnick
oxidation (Scheme 5). The best results were obtained using
Lemieux−von Rudloff oxidation28 conditions to give 25 in 74%
yield. Hydrogenolysis then gave the final product 15 in 92%
yield (Scheme 5).
was a superior solvent compared with either toluene or DMSO.
Changing the catalyst loading failed to improve the yield.
Molecular sieves were added in an attempt to alleviate the
problem of catalyst aggregation22 to no avail. Addition of
Cs2CO3 resulted in polymerization of the starting material.
Further functionalization of 24 was attempted; however,
epoxidation,23 aldehyde-selective Wacker oxidation,24 hydro-
boration−oxidation,25 and allylic oxidation with selenium26
were not effective.
At this point, we hypothesized that the use of the crotyl-
containing monocyclic β-lactam 17b would provide access to a
more readily functionalizable alkene-containing bicyclic β-
lactam, 16 (eq 2). Aza-Wacker conditions from the synthesis
Encouraged by these results, we were interested in seeing
whether this approach would be compatible with syntheses of
C-3-substituted β-lactam analogues. Here we describe results
that include incorporation of a 3-hydroxyethyl side chain,
peripheral functionalization that has been shown to be
important for the activity of carbapenems as previously
illustrated in 6−14. Commercially available 3-hydroxyethyl-4-
acetoxy-β-lactam 26 was allylated with In(s), NaI, and
allylbromide to give 27 (Scheme 6).29 Isomerization of the 4-
30
allyl side chain with RuHCOCl(PPh)3 gave 4-(2-propene)-
substituted compound 28, which was oxidized to 4-carboxylic
acid 2931 with KMnO4/NaIO4. EDC·HCl coupling with N-
crotyl-O-benzylhydroxylamine hydrochloride (20b) gave pend-
ant-alkene-containing β-lactam 30 in fair yield. Treatment of 30
with the optimized conditions from the palladium-catalyzed
cyclization of 16 gave bicyclic product 31 in good yield.
Oxidation of the alkene with KMnO4/NaIO4 gave product 32
containing the carboxylic acid.
Although 15 does not have the α-amido side chain normally
required for antibiotic activity, we screened it against a
representative set of Gram-positive (Bacillus subtilis, Staph-
ylococcus aureus, Micrococcus luteus, Mycobacterium vaccae) and
of 24 gave the desired product 16 as a single diastereomer in
low yield (8%) after an extended reaction time (3 days).
Switching to BQ as the oxidant in acetic acid (100 mol % BQ,
110 mol % AcOH)27 increased the yield to 35%. Finally,
Scheme 5. Elaboration to the Fully Functionalized Core (15)
C
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Scheme 6. Synthesis of C-3-Substituted Bicyclic β-Lactam 32
(S)-N-(Benzyloxy)-N-(but-2-en-1-yl)-4-oxoazetidine-2-car-
boxamide (17b). (S)-4-Carboxy-2-azetidinone (23)20 {[α]D = −46.2
(c = 2.1, CHCl3); lit.20 −43.4 (c = 3.3, CHCl3)} (0.99 g, 8.60 mmol),
hydroxylamine hydrochloride 20b19 (1.83 g, 8.60 mmol), and HOBt
(1.74 g, 12.90 mmol) were suspended in 66 mL of freshly distilled
MeCN. Disopropylamine (3 mL, 17.20 mmol) was added, followed by
EDC·HCl (4.90 g, 25.80 mmol). After 24 h, the mixture was
concentrated under reduced pressure. The crude product was
dissolved in DCM, extracted with 0.5 M citric acid, and then washed
with water and brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. Chromatography with 3:1−4:1 EtOAc/
hexanes gave 17b as an amber oil (1.90 g, 81%). [α]D = −85.0 (c = 3.4,
CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 1.73 (m, 3H), 2.97 (dd, 1H,
J = 14.8, 2.9 Hz), 3.11 (ddd, 1H, J = 14.8, 5.5, 1.2 Hz), 4.21 (dd, 1H, J
= 5.5, 2.9 Hz), 4.29 (m, 2H), 4.83 (s, 2H), 5.55 (m, 1H, J = 8.6, 6.7,
1.7 Hz), 5.75 (m, 1H, J = 8.6, 6.5, 1.2 Hz), 5.88 (br s, 1H), 7.37 (m,
5H) [the crotyl bromide used in the synthesis of 20b was 85% trans;
cis isomer 4.85 (s)]; 13C NMR (100 MHz, CDCl3) δ 18.0, 43.1, 47.2,
48.8, 77.0, 124.3, 129.1, 129.5, 129.6, 131.3, 134.2, 167.0, 171.9 [cis
isomer 13.3, 123.6]; IR (Et2O) ν 1666, 1767 cm−1; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C15H19N2O3 275.1390, found 275.1374.
(S)-4-(Benzyloxy)-2-methylene-1,4-diazabicyclo[4.2.0]-
octane-5,8-dione (24). Pd(OAc)2 (0.03 g, 0.14 mmol) and pyridine
(0.03 mL, 0.28 mmol) were suspended in 8 mL of MeCN. O2 was
bubbled through the solution for 10 min. The lemon-yellow solution
was then heated in an oil bath at 73 °C for 10 min under 1 atm O2. A
solution of (S)-N-allyl-N-(benzyloxy)-4-oxoazetidine-2-carboxamide
(17a) (0.18 g, 0.69 mmol) in 9 mL of MeCN was added. After 8 h,
the mixture was concentrated under reduced pressure. Chromatog-
raphy of the residue with EtOAc/hexanes (2:1) gave 24 as an off-white
solid (0.07 g, 40%). Mp 83−86 °C; [α]D = −60.5 (c = 0.2, CH2Cl2);
1H NMR (400 MHz, CDCl3) δ 3.34 (m, 2H, J = 15.7, 5.1, 3.5 Hz),
Gram-negative (Pseudomonas aeruginosa, Escherichia coli,
Acinetobacter baumannii) bacteria. As expected, bicyclic β-
lactam 15 was not active. Screening of 32 showed that it was
also inactive. Future studies will focus on the incorporation of
additional peripheral functionality. The methodology reported
here should be of considerable general utility for the formation
of bicyclic β-lactams.
CONCLUSIONS
■
We have demonstrated that Pd(II)-catalyzed oxidative
amidation can be applied to highly functionalized β-lactams
to diastereoselectively give a novel bicyclic core. This core can
then be functionalized to give the carboxylic acid in one step.
This methodology is compatible with a C-3 hydroxyethyl side
chain common in carbapenems.
EXPERIMENTAL SECTION
■
General Methods. Reagents and solvents were purchased from
commercial suppliers and used without purification, unless otherwise
noted. 1,4-Benzoquinone was sublimed before use, and MeCN was
distilled over CaH2 for the EDC·HCl couplings. Chromatography was
carried out on 230−400 mesh silica gel. NMR analysis was obtained at
25 °C on a 400, 500, or 600 MHz instrument. Chemical shifts are
given in parts per million relative to residual solvent peaks. High-
resolution mass spectrometry was conducted with electrospray
ionization and a time-of-flight analyzer. Specific rotation ([α]D) was
calculated using (100·α)/(l·c), where the concentration c was in units
of g/100 mL.
(S)-N-Allyl-N-(benzyloxy)-4-oxoazetidine-2-carboxamide
(17a). (S)-4-Oxoazetidine-2-carboxylic acid (23)20 (0.77 g, 6.70
mmol), N-allyl-O-benzylhydroxylamine hydrochloride (20a)18 (1.33
g, 6.70 mmol), and HOBt (1.36 g, 10.01 mmol) were suspended in
freshly distilled MeCN. DIPEA (2.3 mL, 13.40 mmol) was added,
followed by EDC·HCl (3.85 g, 20.10 mmol). After 16 h, the reaction
mixture was concentrated under reduced pressure. The crude product
was dissolved in DCM, extracted with 0.5 M citric acid, and then
washed with H2O and brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. Chromatography with EtOAc/
3.76 (d, 1H, J = 14.8 Hz), 4.18 (dd, 1H, J = 5.1, 3.5 Hz), 4.23 (dt, 1H,
J = 14.9, 1.8 Hz), 4.32 (m, 1H), 5.0 (m, 2H), 5.01 (t, 1H, J = 1.6 Hz)
7.39 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 41.6, 49.8, 54.0, 76.9,
96.5, 129.0, 129.5, 130.0, 134.1, 134.7, 165.0, 166.1; IR (Et2O) ν 1689,
1771 cm−1; HRMS (ESI-TOF) m/z [M]+ calcd for C14H14N2O3
259.1077, found 259.1099.
(2S,6S)-4-(Benzyloxy)-2-vinyl-1,4-diazabicyclo[4.2.0]octane-
5,8-dione (16). Pd(OAc)2 (0.04 g, 0.17 mmol), 1,4-benzoquinone
(0.30 g, 2.75 mmol), and acetic acid (0.15 mL, 2.58 mmol) were
dissolved in 10 mL of MeCN. A solution of (S)-N-(benzyloxy)-N-
(but-2-en-1-yl)-4-oxoazetidine-2-carboxamide (17b) (0.47 g, 1.72
mmol) in 7 mL of MeCN was added, and the bright-orange solution
was heated at 70 °C under air. After 49 h, the reddish-brown
suspension was concentrated under reduced pressure to give a gummy
black solid, which was suspended in DCM and filtered to remove the
catalyst and hydroquinone. Chromatography with a gradient of pure
DCM to 1:1 DCM/ether to ether gave the desired product 16 as an
hexanes (3:1) gave 17a as a pale-yellow oil (1.10 g, 62%). [α]D
=
1
−79.6 (c = 0.9, CH2Cl2); H NMR (400 MHz, CDCl3) δ 2.97 (dd,
1H, J = 14.9, 3.2 Hz), 3.12 (ddd, 1H, J = 14.9, 5.9, 1.6 Hz), 4.24 (dd,
1H, J = 5.5, 2.8 Hz), 4.29 (m, 2H), 4.84 (s, 2H), 5.29 (m, 2H, J = 15.3,
9.4, 1.2 Hz), 5.86 (m, 1H, J = 16.2, 10.3, 6.3 Hz), 6.08 (br s, 1H), 7.37
(m, 5 H); 13C NMR (100 MHz, CDCl3) δ 43.1, 47.1, 49.6, 76.9, 119.6,
129.2, 129.5, 129.6, 131.6, 134.1, 166.8, 172.1; IR (Et2O) ν 1667, 1768
cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C14H17N2O3
261.1234, found 261.1204.
1
amber oil (0.28 g, 60% yield). [α]D = −42.6 (c = 0.8, CH2Cl2); H
D
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NMR (400 MHz, CDCl3) δ 3.15 (dd, 1H, J = 15.7, 2.5 Hz), 3.38 (dd,
1H, J = 12.5, 5.6 Hz), 3.42 (dd, 1H, J = 15.7, 5.9 Hz), 3.68 (dd, 1H, J =
12.5, 5.6 Hz), 4.08 (dd, 1H, J = 5.9, 2.5 Hz), 4.29 (m, 1H, J = 10.3, 5.7,
1.4 Hz), 5.05 (m, 2H), 5.24 (m, 2H, J = 17.0, 10.1, 3.1, 1.2 Hz), 5.48
(ddd, 1H, J = 17.0, 10.1, 4.5 Hz), 7.40 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 42.3, 49.0, 51.9, 54.6, 76.9, 118.7, 129.0, 129.5, 130.1, 132.6,
134.9, 166.8, 169.4; IR (Et2O) ν 1685, 1763 cm−1; HRMS (ESI-TOF)
m/z [M + Na]+ calcd for C15H16N2NaO3 295.1053, found 295.1028.
(2R,6S)-4-(Benzyloxy)-5,8-dioxo-1,4-diazabicyclo[4.2.0]-
octane-2-carboxylic Acid (25). Bicyclic alkene 16 (0.26 g, 0.94
mmol) was dissolved in acetone/water (18 mL/10 mL). The pale-
brown solution was purged with Ar, and then KMnO4 (0.10 g, 0.66
mmol), NaIO4 (1.01 g, 4.70 mmol), and NaHCO3 (0.08 g, 0.94
mmol) were added. After 19 h, the pH was adjusted to 2 with 2 M
HCl, and the solution was filtered through Celite with EtOAc. The
biphasic solution was extracted with EtOAc. The organic fractions
were extracted with 0.1 M Na2SO3. The aqueous fractions were
adjusted to pH 2 with 3 M HCl and extracted with EtOAc. The
organic fractions were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure to give the desired product 25 as
an off-white foam (0.20 g, 74%). 1H NMR (400 MHz, CD3OD) δ 3.09
(dd, 1H, J = 15.5, 2.6 Hz), 3.45 (dd, 1H, J = 15.5, 5.7 Hz), 3.91 (dd,
1H, J = 12.2, 4.7 Hz), 4.00 (dd, 1H, J = 12.6, 6.3 Hz), 4.26 (dd, 1H, J =
5.9, 2.4 Hz), 4.62 (dd, 1H, J = 6.3, 4.3 Hz), 4.95 (m, 2H), 7.41 (s,
5H); 13C NMR (100 MHz, CDCl3) δ 43.1, 49.4, 51.3, 52.1, 76.9,
129.0, 129.6, 130.0, 134.4, 167.0, 169.1, 170.0; IR (Et2O) ν 1679, 1749
cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C14H14N2NaO5
313.0795, found 313.0786.
(2R,6S)-4-Hydroxy-5,8-dioxo-1,4-diazabicyclo[4.2.0]octane-
2-carboxylic Acid (15). Bicyclic carboxylic acid 25 (0.20 g, 0.69
mmol) was dissolved in 8 mL of peroxide-free THF. The pale-yellow
solution was purged with Ar. Pd/C (10% Pd, 0.02 g, 0.02 mmol of Pd)
was added, and the black suspension was degassed under vacuum. The
reaction flask was purged with hydrogen, and the hydrogen
atmosphere was maintained with a hydrogen balloon. After 2 h, the
suspension was purged with Ar, filtered through glass filter paper with
MeOH, and concentrated to give 15 as a white foam (0.13 g, 92%). 1H
NMR (400 MHz, CD3OD) δ 3.11 (dd, 1H, J = 15.4, 2.5 Hz), 3.49 (dd,
1H, J = 15.4, 5.9 Hz), 4.00 (dd, 1H, J = 12.7, 3.1 Hz), 4.17 (dd, 1H, J =
12.4, 6.2 Hz), 4.29 (dd, 1H, J = 6.0, 2.4 Hz), 4.86 (dd, 1H, J = 6.1, 3.0
Hz); 13C NMR (100 MHz, CD3OD) δ 42.1, 48.5, 51.0, 52.8, 166.3,
169.5, 169.8; IR (Et2O) ν 1654, 1747 cm−1; HRMS (ESI-TOF) m/z
[M − H]− calcd for C7H7N2O5 199.0360, found 199.0340.
organic fractions were extracted with NaHSO3 and brine, dried over
MgSO4, filtered, and concentrated under vacuum to give an oily yellow
1
solid (0.08 g, 84%). [α]D = −13.0 (c = 0.3, MeOH); H NMR (500
MHz, CDCl3) δ 0.09 (d, 6H, J = 6.6 Hz), 0.88 (s, 9H), 1.26 (d, 3H, J =
6.4 Hz), 3.36 (td, 1H, J = 2.7, 1.2 Hz), 4.32 (ddd, 1H, J = 12.5, 6.4, 2.7
Hz), 4.38 (dd, 1H, J = 2.2, 0.5 Hz), 6.23 (s, 1H); 13C NMR (125
MHz, CDCl3) δ −5.0, −4.1, 18.2, 22.5, 25.9, 29.9, 49.3, 64.2, 64.9,
169.4, 175.6; IR (Et2O) ν 1643, 1751 cm−1; HRMS (ESI-TOF) m/z
[M − H]− calcd for C12H22NO4Si 272.1324, found 272.1325.
(2S,3S)-N-(Benzyloxy)-N-(but-2-en-1-yl)-3-((R)-1-((tert-
butyldimethylsilyl)oxy)ethyl)-4-oxoazetidine-2-carboxamide
(30). N-Crotyl-O-benzylhydroxylamine hydrochloride (20b) (0.16 g,
0.73 mmol), HOBt (0.15 g, 1.10 mmol), cat. DMAP, and carboxylic
acid 29 (0.20 g, 0.73 mmol) were suspended in 10 mL of freshly
distilled MeCN under Ar. Hunig’s base (0.25 mL, 1.46 mmol) was
added, followed by EDC·HCl (0.42 g, 2.20 mmol). After 24 h, the
mixture was concentrated under vacuum; diluted with DCM; extracted
with 0.5 M citric acid (×2), 4% NaHCO3 (×2), water, and brine; dried
over MgSO4; filtered; and reduced to give an amber oil. Column
chromatography on silica gel with 1:1 hexanes/EtOAc gave a waxy
1
pale-amber solid (0.17 g, 54%). [α]D = −1.4 (c = 1.6, CH2Cl2); H
NMR (400 MHz, CDCl3) δ 0.06 (s, 6H), 0.89 (s, 9H), 1.11 (d, 3H, J
= 6.3 Hz), 1.72 (dd, 3H, J = 6.3, 1.6 Hz), 3.34 (td, 1H, J = 2.4, 1.2 Hz),
4.15−4.35 (m, 3H), 4.39 (dd, 1H, J = 5.5, 2.4 Hz), 4.86 (s, 2H), 5.51
(m, 1H, J = 12.6, 6.3, 1.6 Hz), 5.62 (br s, 1H), 5.75 (ddd, 1H, J = 13.0,
6.3, 1.2 Hz), 7.31−7.43 (m, 5H); 13C NMR (100 MHz, CDCl3) δ
−4.9, −4.1, 13.3, 18.0, 18.2, 22.5, 26.0, 43.4, 48.2, 48.3, 48.6, 63.6, 64.2,
76.9, 123.8, 124.5, 129.0, 129.3, 129.5, 129.6, 131.0, 133.9, 168.5, 171.7
[mix of cis (minor) and trans (major) isomers]; IR (Et2O) ν 1653,
1749 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C23H37N2O4Si
433.2517, found 433.2534.
(6S,7S)-4-Benzyloxy-7-((R)-1-((tert-butyldimethylsilyl)oxy)-
ethyl)-2-vinyl-1,4-diazabicyclo[4.2.0]octane-5,8-dione (31). Pal-
ladium acetate (0.02 g, 0.07 mmol), benzoquinone (0.06 g, 0.52
mmol), and acetic acid (0.03 mL, 0.49 mmol) were dissolved in 1 mL
of MeCN. (2S,3S)-N-(Benzyloxy)-N-(but-2-en-1-yl)-3-((R)-1-((tert-
butyldimethylsilyl)oxy)ethyl)-4-oxoazetidine-2-carboxamide (30)
(0.14 g, 0.33 mmol) in 3 mL of MeCN was added. The flask
containing the solution was placed in an oil bath at 45 °C. After 48 h,
the reaction mixture was concentrated under vacuum; diluted with
DCM; extracted with 10% NaHSO3 (×3), 4% NaHCO3 (×3), and
brine; dried over MgSO4; filtered; and concentrated to give a pale-tan
oil. Chromatography with 2:1 hexanes/EtOAc gave a pale-yellow oil
(0.08 g, 54%). [α]D = −36.3 (c = 0.8, CH2Cl2); 1H NMR (500 MHz,
CDCl3) δ 0.05 (s, 3H), 0.08 (s, 3H), 0.87 (s, 9H), 1.28 (d, 3H, J = 6.4
Hz), 3.33 (t, 1H, J = 2.5 Hz), 3.37 (dd, 1H, J = 12.2, 4.9 Hz), 3.71 (dd,
1H, J = 12.2, 5.6 Hz), 4.20 (d, 1H, J = 2.7 Hz), 4.30−4.37 (m, 2H),
4.95−5.02 (m, 2H), 5.21 (dq, 1H, J = 10.3, 1.0 Hz), 5.28 (dq, 1H, J =
17.1, 1.0 Hz), 5.46 (ddd, 1H, J = 17.1, 10.3, 4.7 Hz), 7.35−7.45 (m,
5H); 13C NMR (125 MHz, CDCl3) δ −4.8, −4.4, 18.2, 22.7, 25.9,
26.0, 29.9, 50.3, 51.3, 54.8, 63.8, 64.0, 76.9, 118.6, 128.9, 129.4, 130.1,
132.8, 135.0, 167.3, 169.7; IR (Et2O) ν 1683, 1766 cm−1; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C23H35N2O4Si 431.2361, found
431.2352.
(3S,4R)-3-((R)-1-((tert-Butyldimethylsilyl)oxy)ethyl)-4-(prop-
1-en-1-yl)azetidin-2-one (28). (3S,4R)-4-Allyl-3-((R)-1-((tert-
butyldimethylsilyl)oxy)ethyl)azetidin-2-one (27) (0.20 g, 0.74
mmol) was dissolved in 7 mL of freshly distilled THF, and the
suspension was purged with Ar for 10 min. RuHCOCl(PPh3)3 (0.06 g,
0.07 mmol) was added, and the reaction mixture was heated in an oil
bath at 76 °C. After 4 h, the solution was concentrated under vacuum
and chromatographed on silica gel with 2:1 hexanes/EtOAc to give a
1
waxy brown solid (0.17 g, 85%). [α]D = −14.1 (c = 0.8, CH2Cl2); H
NMR (400 MHz, CDCl3) δ 0.08 (s, 6H), 0.88 (s, 9H), 1.20 (d, 3H, J
= 6.3 Hz), 1.71 (d, 3H, J = 6.7 Hz), 2.84 (m, 1H, J = 2.7, 1.9, 0.9 Hz),
4.14 (d, 1H, J = 7.5 Hz), 4.21 (qd, 1H, J = 6.3, 4.7 Hz), 5.55 (m, 1H, J
= 7.8, 1.2 Hz), 5.73 (m, 1H, J = 14.6, 6.3 Hz), 5.82 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ −4.8, −4.0, 13.5, 17.8, 18.2, 22.6, 25.9, 39.7,
46.2, 50.4, 52.1, 64.0, 64.9, 65.6, 65.7, 65.9, 66.3, 118.2, 128.2, 128.5,
130.3, 130.9, 168.9 [mix of cis (minor) and trans (major) isomers]; IR
(Et2O) ν 1642 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C14H28NO2Si 270.1884, found 270.1881.
(6S,7S)-4-(Benzyloxy)-7-((R)-1-((tert-butyldimethylsilyl)oxy)-
ethyl)-5,8-dioxo-1,4-diazabicyclo[4.2.0]octane-2-carboxylic
acid (32). (6S,7S)-4-(Benzyloxy)-7-((R)-1-((tert-butyldimethylsilyl)-
oxy)ethyl)-2-vinyl-1,4-diazabicyclo[4.2.0]octane-5,8-dione (18) (0.04
g, 0.09 mmol) was dissolved in acetone/water (3 mL/1 mL), and the
solution was purged with Ar for 10 min. Potassium permanganate
(0.01 g, 0.07 mmol), sodium periodate (0.10 g, 0.47 mmol), and
sodium bicarbonate (0.01 g, 0.09 mmol) were added in one portion.
After 17 h, the reaction was quenched with 10% NaHSO3, and the
mixture was extracted with EtOAc (×3). The combined organic
fractions were washed with 10% NaHSO3 and brine, dried over
MgSO4, filtered, and concentrated to give a clear glass (0.03 g, 78%).
(2S,3S)-3-((R)-1-((tert-Butyldimethylsilyl)oxy)ethyl)-4-oxoa-
zetidine-2-carboxylic acid (29). (3S,4R)-3-((R)-1-((tert-
Butyldimethylsilyl)oxy)ethyl)-4-(prop-1-en-1-yl)azetidin-2-one (28)
(0.09 g, 0.33 mmol) was dissolved in acetone/water (6 mL/2 mL).
Potassium permanganate (0.04 g, 0.23 mmol), sodium periodate (0.35
g, 1.66 mmol), and sodium bicarbonate (0.06 g, 0.66 mmol) were
added in one portion. After 19 h, the mixture was treated with
NaHSO3 until the purple suspension became clear yellow. The
aqueous solution was extracted with EtOAc (×4). The combined
1
[α]D = −7.6 (c = 0.4, CH2Cl2); H NMR (500 MHz, CDCl3) δ 0.04
(s, 3H), 0.07 (s, 3H), 0.86 (s, 9H), 1.28 (d, 3H, J = 6.4 Hz), 3.39 (d,
1H, J = 5.1 Hz), 3.78 (dd, 1H, J = 12.2, 3.9 Hz), 3.88 (dd, 1H, J = 12.2,
6.1 Hz), 4.32 (qd, 1H, J = 6.2, 2.2 Hz), 4.41 (d, 1H, J = 2.7 Hz), 4.54
E
dx.doi.org/10.1021/jo402544p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(dd, 1H, J = 6.1, 3.9 Hz), 4.90−5.02 (m, 2H), 7.34−7.42 (m, 5H); 13
C
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NMR (125 MHz, CDCl3) δ −5.0, −4.2, 18.1, 22.6, 25.8, 25.9, 29.9,
50.8, 50.9, 52.5, 63.7, 65.0, 77.0, 129.0, 129.5, 130.0, 131.1, 134.6,
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m/z [M − H]− calcd for C22H31N2O6Si 447.1957, found 447.1924.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Persson, A. K. A.; Millet, R.; Johnson, M. T.; Backvall, J.-E. Chem.
̈
Eur. J. 2012, 18, 15151.
AUTHOR INFORMATION
Corresponding Author
*E-mail: mmiller1@nd.edu.
Notes
(18) Sulsky, R.; Demers, J. P. Tetrahedron Lett. 1989, 30, 31.
(19) Yoshioka, E.; Kohtani, S.; Sawai, K.; Kentefu; Tanaka, E.;
Miyabe, H. J. Org. Chem. 2012, 77, 8588.
(20) (a) Literature reference for 23: Baldwin, J. E.; Adlington, R. M.;
Gollins, D. W.; Schofield, C. J. Tetrahedron 1990, 46, 4733. (b)
Experimental modifications: Lynch, J. K.; Holladay, M. W.; Ryther, K.
B.; Bai, H.; Hsiao, C. N.; Morton, H. E.; Dickman, D. A.; Arnold, W.;
King, S. A. Tetrahedron: Asymmetry 1998, 9, 2791.
(21) Fix, S. R.; Brice, J. L.; Stahl, S. S. Angew. Chem., Int. Ed. 2002, 41,
164.
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(23) Parsons, P. J.; Camp, N. P.; Underwood, M.; Harvey, D. M.
Tetrahedron 1996, 52, 11637.
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Chem. Soc. 2009, 131, 9473.
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Eli Lilly for supporting this research through
a graduate fellowship to M.O.J. We also gratefully acknowledge
Patricia Miller (UND) for antibacterial assays, Nonka Sevova
and Dr. Bill Bogges (Mass Spectrometry and Proteomics
Facility, UND) for mass spectroscopic analyses, and Dr.
Jaroslav Zajicek (Lizzadro Magnetic Resonance Research
Center, UND) for NMR assistance.
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(26) (a) Sharpless, K. B.; Verhoeven, T. R. Aldrichimica Acta 1979,
12, 63. (b) Rao, A. V. R.; Gurjar, M. K.; Khare, V. B.; Ashok, B.;
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