Diversification of a β-lactam pharmacophore via allylic C-H amination: Accelerating effect of Lewis acid co-catalyst

Article abstract of DOI:10.1016/j.tet.2010.04.064

This report describes the use of Pd(II)/bis-sulfoxide 1 catalyzed intra- and intermolecular allylic C-H amination reactions to rapidly diversify structures containing a sensitive β-lactam core similar to that found in the monobactam antibiotic Aztreonam.

Full text of DOI:10.1016/j.tet.2010.04.064

Tetrahedron 66 (2010) 4816e4826
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journal homepage: www.elsevier.com/locate/tet
Diversification of a
b-lactam pharmacophore via allylic CeH amination:
accelerating effect of Lewis acid co-catalyst
,
Xiangbing (Ben) Qi a, Grant T. Rice a, Manjinder S. Lall b, Mark S. Plummer b, M. Christina White a
*
a Roger Adams Laboratory, Department of Chemistry, University of Illinois, 600 South Mathews, Urbana, IL 61801, USA
b Pfizer Global Research and Development, 445 Eastern Point Road, Groton, Connecticut 06340, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
This report describes the use of Pd(II)/bis-sulfoxide 1 catalyzed intra- and intermolecular allylic CeH
amination reactions to rapidly diversify structures containing a sensitive -lactam core similar to that
Received 26 March 2010
Received in revised form 14 April 2010
Accepted 15 April 2010
b
found in the monobactam antibiotic Aztreonam. Pharmacologically interesting oxazolidinone, ox-
azinanone, and linear amine motifs are rapidly installed with predictable and high selectivities under
conditions that use limiting amounts of substrate. Additionally, we demonstrate for the first time that
intramolecular CeH amination processes may be accelerated using catalytic amounts of a Lewis acid co-
catalyst [Cr(III)(salen)Cl 2].
Available online 21 April 2010
Dedicated to Professor Brian Stoltz in cele-
bration of his receiving the Tetrahedron
Young Investigator Award
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
The most prevalent means of generating diversity among a com-
mon molecular skeleton follows the modern synthetic planning
paradigm that relies on the manipulation of ‘reactive’ oxidized
functionality. In medicinal chemistry, a molecule containing a phar-
macophoric unit (i.e., structural feature in a molecule responsible for
its biological activity) may be subjected to a series of orthogonal
functionalizations of pre-existing reactive sites with the expectation
of refining or improving biological activity and/or therapeutic pro-
files. The introduction of new functionality using ubiquitous and
inert CeH bonds presents an opportunity for a powerful new mode
of accessing diversity.1 Methods are emerging that directly transform
CeH bonds into CeO, CeN, or CeC bonds.2 We have developed
methods using Pd(II)/bis-sulfoxide catalyst 1 that allow oxygen,3
nitrogen4 and carbon functionalities5 to be installed directly from
allylic CeH bonds and demonstrated that these reactions can be
strategically employed at late stages in complex molecule syntheses
to streamline the route and improve overall yields.6 Given that these
CeH functionalizations proceed with predictable and high selectiv-
ities in complex molecule settings, we anticipated that they could be
used to diversify structures containing reactive pharmacophoric
units such as
b-lactams (azetidin-2-ones, Fig. 1).
Figure 1. Diversification of a b-lactam pharmacophore via allylic CeH amination.
b
-Lactams (azetidin-2-ones) are reactive functionality often
cephalosporins, carbopenems, and monobactams) and are also key
elements in three clinically used -lactamase inhibitors tazo-
used as mechanism based inhibitors for enzymes that employ an
active site serine nucleophile, forming an acyl enzyme adduct.
Molecules containing the b-lactam structural unit are fundamental
b
bactam, clavulinic acid, and sulbactam. The monobactam antibiotic,
aztreonam, has structural similarity with our azetidin-2-one core
(Fig. 1). Furthermore, azetidin-2-ones have appeared in pharma-
ceutical agents for cholesterol absorption inhibition, thrombin in-
to many classes of antibiotics in clinical use (e.g., penicillins,
* Corresponding author. E-mail address: white@scs.uiuc.edu (M.C. White).
hibition, and prostate specific antigen inhibition.7
b-lactams have
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.064

X.(Ben) Qi et al. / Tetrahedron 66 (2010) 4816e4826
4817
also found increased use as synthons because stereocenters can be
readily defined through asymmetric ketene-imine cycloadditions
and the strained cyclic structure can be easily opened via acid and
base catalyzed carbonyl ring openings.8 However, the high strain-
energy associated with the four-membered azetidin-2-one ring
makes derivatizations in the presence of this core challenging.9
The prevalence of nitrogen functionality in biologically important
small molecules, along with the extensive functional group manip-
ulations (FGMs) commonlyemployed to install nitrogen, underscores
the potential utility of direct CeH to CeN bond forming reactions for
increasing product diversity. We recently reported Pd(II)/bis-sulfox-
ide-catalyzed allylic CeH aminations that furnish either branched4b,e
or linear allylic amines4c,f directly from terminal olefins with pre-
dictable and high regio- and chemoselectivities. We anticipated that
these allylic CeH amination reactions would provide a highly effi-
cient means of introducing pharmacologically interesting nitrogen
functionality (i.e., oxazolidinones, oxazinanones, linear amines)10
source of weak base is regenerated during oxidation of Pd(0) with
quinone (Fig. 2C). Lowering the pKa of the nitrogen promotes catalysis
by increasing the equilibrium concentration of active anionic species
without prohibitively decreasing its nucleophilicity.4e For example,
switching from N-tosyl carbamates to N-nosyl carbamates (N-(4-
nitrophenylsulfonyl) carbamates) resulted in significantly faster re-
action times for furnishingoxazolidinones (72/24 h) and a dramatic
improvement in yield for furnishing oxazinanone products (6%/
62%), (Table 1A, entries 1 and 2; Table 1B, entries 1 and 2).4e
The mild strategy of harnessing palladium carboxylate coun-
terions as a source of endogenous base to promote functionaliza-
tion
proved
ineffective
for
promoting
intermolecular
functionalization (Fig. 2C). We have alternatively delineated two
general strategies for promoting intermolecular functionalization
with N-tosyl carbamate nucleophiles. One strategy involves the
addition of exogenous Brønsted base (e.g., N,N-diisopropylethyl-
amine, DIPEA) in catalytic amounts to increase the concentration of
deprotonated nitrogen nucleophile in solution,4f and the second
involves using a Lewis acid co-catalyst [Cr(III)(salen)Cl 2]4c,12 that
onto molecules containing sensitive b-lactam cores (Fig. 1).
acts with a
p-acidic ligand (e.g., p-benzoquinone, BQ) to activate
2. Results
electrophilic
p-allylPd intermediates toward nucleophilic attack
(Fig. 2B). We hypothesized that Lewis acid activation may have
a beneficial effect on intramolecular allylic CeH amination re-
actions by increasing the rate of functionalization. This may be-
come particularly important for densely functionalized substrates
where steric and/or electronic factors slow down functionalization.
Consistent with this hypothesis, we found that the addition of
catalytic amounts of Cr(III)(salen)Cl 2 (6 mol %) appreciably short-
ened the reaction times of both the 1,2- and 1,3- intramolecular
allylic CeH amination reactions (Table 1). Significantly, for
Allylic CeH amination reactions face significant chemoselectivity
and reactivity issues that must be overcome to effect catalysis. In
palladium-mediated processes, addition of the nitrogen nucleophile
to the olefin (aminopalladation) is generally the dominant pathway.11
Moreover, common strategies for promoting functionalization, i.e.,
use of stoichiometric anionic nucleophiles and strong
s-donating
ligands, are incompatible with electrophilic Pd(II)-mediated CeH
cleavage. We reported that bis-sulfoxide/Pd(OAc)2 catalyst 1 pro-
motes intramolecular allylic CeH amination with weak carbamate
nucleophiles to furnish oxazolidinone (1,2 CeH amination4b) and
oxazinanone (1,3 CeH amination4e) structures in good yields and
preparatively useful diastereoselectivities (Fig. 1). Key to this re-
activity is the bis-sulfoxide ligand that diverts aminopalladation and
Table 1
The effect of Lewis Acid Additive [Cr(III)(salen)Cl] on Intramolecular Allylic CeH
aminations
Entry
R
Additive (6 mol %) Timea (h) Isolated yieldb (%) drc
promotes Pd-mediated heterolytic CeH cleavage to furnish p-allylPd
intermediates (Fig. 2A). Intramolecular functionalization with the
acidic carbamate pro-nucleophile is promoted by the palladium
carboxylate counterion acting as a base (Fig. 2B).4b This catalytic
1
2
3
p-Tol
None
72
24
6
76
78
80
6:1
5:1
4:1
p-NO2Ph None
p-NO2Ph Cr(salen)CI 2d
1
2
3
4
p-Tol
p-NO2Ph None
p-Tol
p-NO2Ph
p-NO2Ph None
p-NO2Ph
p-NO2Ph
None
72
24
5
2.5
24
1.5
1.5
6
62
77
87
80
89
9g
5:1
4:1
4:1
3:1
6:1
4:1
d
2
2
5e
6e
7f
2
2
a
All reactions were run to complete conversion.
b
c
Generally, average of two runs, see Supplementary data (SI).
Determined by GC analysis (R¼p-Tol) or 1H NMR analysis (R¼p-NO2Ph) of crude
reaction mixture.
d
Cr(salen)CI¼(1R,2R)-(ꢀ)-[1,2-Cyclohexanediamino-N,N0-bis(3,5-di-tert-
butylsalicylidene)]chromium(III) chloride.
e
Optimized conditions for 1,3-amination reaction: Cat.
1 (10 mol %), PhBQ
(2 equiv), BisSO (5 mol %), oxygenated DCE (0.66 M), p-nitrobenzoic acid (10 mol%).
f
Conditions: Cat.
1 (10 mol %), 2,5-dimethylbenzoquinone (2 equiv); BisSO
(5 mol %), oxygenated DCE (0.66 M), p-nitrobenzoic acid (10 mol%).
g
Yield determined through 1H NMR analysis (81% remaining starting material).
Figure 2. Design principles for allylic CeH amination.

4818
X.(Ben) Qi et al. / Tetrahedron 66 (2010) 4816e4826
substrates containing the N-tosyl carbamate nucleophile, a dra-
matic positive impact was observed on both the reaction time
(72/5 h) and yield (6/77%) of six-membered ring product for-
mation (Table 1B, entries 1 and 3). Substrates having an N-nosyl
carbamate nucleophile showed an improvement in reaction times
for furnishing both a 5- and six-membered ring (24/6 h, Table 1A,
entries 2 and 3; 24/2.5 h, Table 1B, entries 2 and 4, respectively),
albeit with a modest decrease in diastereoselectivity (5:1/4:1,
Table 1A, entries 2 and 3; 4:1/3:1, Table 1B, entries 2 and 4, re-
spectively). Under optimized conditions for six-membered ring
product formation, the Cr(salen)Cl 2 additive maintained a signifi-
cant positive impact on reaction times and yields (24/1.5 h,
80/89% yield; Table 1B, entries 5 and 6). All reactions in Table 1
were run to complete conversion; moreover, significant decreases
in yields and diastereoselectivities were observed when Cr-accel-
erated reactions were run past completion. Consistent with our
forming five-membered oxazolidinone products can be overcome
through the inclusion of catalytic [Cr(III)(salen)Cl 2].
In contrast, we previously noted that reactivity and selectivity
for generating six-membered oxazinanones via intramolecular
allylic CeH amination was not strongly impacted by the steric bulk
adjacent to the carbamate.4e Consistent with this, we found that
b-lactam-containing bis-homoallylic N-nosyl carbamate substrate
(ꢀ)-9 furnished oxazinanone (þ)-10 in high yields (76%) and pre-
paratively useful diastereoselectivities (6:1, syn/anti) (Table 2B,
entry 1). The inclusion of [Cr(III)(salen)Cl 2] led to a 4-fold decrease
in reaction times (24/6 h), that was accompanied by a reduction
in diastereoselectivity (3:1, syn/anti) (Table 2B, entry 2). This result
suggests that while the addition of Lewis acid is valuable in in-
creasing reactivity in oxazinanone formation (Table 1B, entry 3, 4
and 6), the improved reaction times must be balanced by a decrease
in diastereoselectivity. It is significant to note, however, that in all
cases diastereomerically pure syn- and anti-oxazinanone products
can be obtained using standard column chromatography.
proposal that the Lewis acid system requires one
p-face of the
quinone to be sterically unhindered for promoting functionaliza-
tion,4f 2,5-dimethylbenzoquinone under optimized Cr(salen)Cl 2
conditions resulted in only trace product formation at 1.5 h (9%,
Table 1B, entry 7).
Finally, we evaluated the linear allylic amination reaction under
both Brønsted base and Lewis acid activation conditions. We found
that the reactivity improves as the terminal olefin is moved further
Reactivity and selectivity trends for Pd/bis-sulfoxide-catalyzed
allylic CeH aminations that have been elucidated on simple sub-
strates are predictive for complex substrates. This is powerfully
demonstrated when evaluating the allylic CeH amination reaction
from the
b
-lactam core. The DIPEA-promoted intermolecular allylic
-lactam-
amination reaction showed sluggish reactivity with
b
containing homoallylic acetate substrate 11 (1:1 dr) furnishing
(E)-linear amine product 12 (1:1 dr; neither the Z or the branched
isomers could be detected by 1H NMR) in 55% yield with substantial
amounts of starting material remaining even after 72 h (28% re-
covered starting material, rsm, Fig. 3). In contrast, bishomoallylic
for diversifying structures containing sensitive
b-lactam cores.
Homoallylic N-nosyl carbamate substrate (ꢀ)-7 gave a modest 46%
yield of oxazolidinone (ꢀ)-8 even after 72 h (Table 2A, entry 1). This
result is consistent with our previous observations that reactivity
and selectivity for intramolecular allylic CeH amination is strongly
impacted by steric bulk adjacent to the carbamate when generating
five-membered oxazolidinones. Specifically, in the case of sterically
congested substrates, the diastereoselectivity is high but the re-
activity is low even after incorporation of a more acidic N-nosyl
carbamate group.4e Importantly, the inclusion of catalytic amounts
of [Cr(III)(salen)Cl 2] (6 mol %) to this reaction resulted in a sub-
stantial increase in yield (46/76%) and improvement in reaction
time (72/24 h) for furnishing anti-oxazolidinone (ꢀ)-8 (Table 2A,
entry 2). The CeH amination is highly diastereoselective; the syn-
oxazolidinone diastereomer could not be detected in 1H NMR
analysis of the crude. Significantly, this result suggests that in some
cases steric limitations for the allylic CeH amination reaction in
substrate (ꢀ)-13 in which the
b-lactam functionality is further re-
moved from the allyl moiety, showed significantly higher reactivity
for DIPEA-base promoted linear allylic CeH amination, furnishing
(þ)-14 in 69% yield. As was previously reported,4f [Cr(III)(salen)Cl 2]
conditions generally do not provide an improvement in product
yields over the Brønsted base conditions for intermolecular allylic
CeH aminations. Subjecting substrate 11 to the Cr conditions
resulted in poor and variable yields of product formation. Impor-
tantly, these reactions were conducted using limiting amounts of
starting material, a distinguishing feature of this intermolecular
CeH amination process that enables its use for diversification of
complex pharmacophoric structures. The importance of using
1 equiv of starting olefin is underscored here, as a 14-step sequence
is required to synthesize
(ꢀ)-9, 11, and (ꢀ)-13 (see Supplementary data).
b
-lactam containing compounds (ꢀ)-7,
Table 2
Diversifying
aminations
b-Lactam containing molecules with intramolecular allylic CeH
Entry
Additive (6 mol %)
Time (h)
Isolated yield (%)
dra
1
2
d
72
24
46
76
>20:1b
>20:1b
Cr(salen)CI 2
Figure 3. Diversifying b-Lactam containing molecules with intermolecular allylic CeH
aminations.
1
2
d
24
6
76
81
6:1
3:1
N-nosyl oxazolidinone (ꢀ)-8 and N-nosyl oxazinanone (þ)-10
were easily deprotected using very mild K2CO3/PhSH conditions in
>90% yields to their corresponding heterocycles (Fig. 4). Signifi-
cantly, oxazolidinones and oxazinanones are important
Cr(salen)CI 2
a
Determined by 1H NMR analysis of crude reaction mixture.
b
Minor syn diastereomer not observed by 1H NMR analysis.

X.(Ben) Qi et al. / Tetrahedron 66 (2010) 4816e4826
4819
heterocycles that can be transformed to aminoalcohol motifs and
are present in biologically active compounds. For example, oxazo-
lidinones are the key structural unit in a new class of synthetic
antibacterial agents for treatment of multi-drug resistant Gram-
positive bacterial infections (e.g., Linezolid).10 Linear allylic amines
12 and (þ)-14 were also easily deprotected using similarly mild Na/
naphthalene conditions in 84% and 89% yield, respectively.
layer chromatography (TLC) was conducted with E. Merck silica
gel 60 F254 precoated plates (0.25 mm) and visualized with UV,
potassium permanganate, ceric ammonium molybdate, and nin-
hydrin staining. Flash column chromatography was performed by
using ZEOprep 60 ECO 43e60 micron silica gel (American In-
ternational Chemical, Inc.). 1H NMR spectra were recorded on
a Varian Unity-400 (400 MHz), Varian Inova-500 (500 MHz), or
Varian Unity-500 (500 MHz) spectrometer and are reported in ppm
using solvent as an internal standard (CHCl3 at 7.26 ppm). Data
reported as: s¼singlet, d¼doublet, t¼triplet, q¼quartet, p¼quintet,
m¼multiplet, b¼broad, app.¼apparent; coupling constant(s) in Hz;
integration. Proton-decoupled 13C NMR spectra were recorded on
a Varian Unity-400 (100 MHz) or Varian Unity-500 (125 MHz)
spectrometer and are reported in ppm using solvent as an internal
standard (CDCl3 at 77.16 ppm). Diastereoselectivity of the allylic
amination reactionwas determined by 1H NMR analysis of the crude
reaction mixture unless otherwise noted. IR spectra were recorded
as thin films on NaCl plates on a Mattson Galaxy Series FTIR 5000
and are reported in frequency of absorption (cmꢀ1). High-resolution
mass spectra were obtained at the University of Illinois Mass
Spectrometry Laboratory. Optical rotations were obtained using
a JASCO DIP-360 digital polarimeter and a 3.5ꢂ50 mm cell and are
ꢁ
reported as follows: [
a
]
l
T C (c¼g/100 mL, solvent).
Figure 4. Removal of N-nosyl and N-tosyl motifs in the presence of sensitive
functionality.
4.2. The effect of Lewis acid additive [Cr(III)(salen)Cl] on
intramolecular allylic CeH aminations (Table 1)
3. Summary and conclusions
4.2.1. Table 1A entries 1 and 2 and Table 1B entry 5. See Ref. 4e for
experimental data and spectral information regarding compounds
3a, 3b, 4a, 4b, 5a, 5b, 6a, and 6b.
The Pd(II)/bis-sulfoxide 1 catalyzed intra- and intermolecular
allylic CeH amination reactions are shown to proceed with pre-
dictable and high selectivities for introducing pharmacologically
interesting oxazolidinones, oxazinanones, and linear amines to
4.2.2. Table 1A entry 3. A one dram vial (topped with a Teflon-
lined cap) was charged with the 2-methylhex-5-en-3-yl tosyl-
carbamate (102.6 mg, 0.30 mmol, 1.0 equiv) and THF (0.45 mL,
0.66 M). The following solids were all first weighed to wax paper
then sequentially added to the vial: Pd(OAc)2/bis-sulfoxide cata-
lyst 1 (15.1 mg, 0.03 mmol, 0.1 equiv), 1,2-bis(phenylsulfinyl)eth-
ane (4.2 mg, 0.015 mmol, 0.05 equiv), Cr(III)(salen)Cl (11.4 mg,
0.018 mmol, 0.06 equiv), and phenylbenzoquinone (58.0 mg,
0.32 mmol, 1.05 equiv). The reaction was finally charged with a stir
bar, topped with a Teflon-lined cap and allowed to stir at 45 ꢁC.
After 6 h the reaction mixture was transferred to a separatory
funnel and diluted with CH2Cl2 (25 mL). Saturated NH4Cl (5 mL)
and brine (5 mL) were added and the aqueous and organic layers
were separated. The aqueous layer was extracted with CH2Cl2
(3ꢂ25 mL). The combined organic layers were dried over MgSO4,
filtered, and concentrated in vacuo. The diastereoselectivity was
obtained by 1H NMR analysis of the crude reaction mixture. Pu-
rification by flash chromatography provided a mixture of syn- and
anti-oxazolidinone products. Run 1 (82 mg, 0.24 mmol, 80% yield
[4.0:1 dr]); run 2 (81 mg, 0.24 mmol, 79% yield [4.0:1 dr]); Average
yield: 80%, 4.0:1 dr (anti/syn).
substrates containing sensitive
b-lactam functionality. This un-
derscores the potential for using such allylic CeH functionaliza-
tion reactions to rapidly introduce new functionality in any
molecule of biological interest that is amenable to appendage with
an allyl unit. Additionally, we demonstrate for the first time that
Lewis acid additive [Cr(III)(salen)Cl 2], may act as a co-catalyst to
accelerate intramolecular allylic CeH amination processes, pre-
sumably by increasing the rates of functionalization. This effect
may be used to shorten reaction times and to overcome the steric
limitations previously noted in furnishing five-membered
oxazolidinones.
4. Experimental
4.1. General information
The following commercially obtained reagents for the allylic
amination reactionwere used as received: N,N-diisopropylethylamine
(DIPEA, Aldrich), (þ)-(R,R)-Cr(salen)Cl (Strem Chemicals),
p-benzoquinone (SigmaeAldrich), 2,5-dimethylbenzoquinone
(Acros Organics), tert-butyl methyl ether (TBME, anhydrous), and
1,2-dichloroethane (DCE), (SigmaeAldrich). Dry Solvents tetrahy-
drofuran (THF), methylene chloride (CH2Cl2), dimethylformamide
(DMF), and diethyl ether (Et2O), were purified prior to use by
passage through a bed of activated alumina (Glass Contour, Laguna
Beach, California). Catalyst A was prepared according to the pub-
lished procedure and stored in a glove box under an argon atmo-
sphere at ꢀ20 ꢁC then weighed out in the air prior to use. All allylic
amination reactions were run under oxygen or ambient air with no
precautions taken to exclude moisture. All other reactions were run
over a stream of nitrogen gas with dry solvent in flame-dried
glassware unless otherwise stated. Solvents were removed by ro-
tatory evaporation at ca. 40 Torr, unless otherwise stated. Thin-
4.2.3. Table 1B entry 1. A one dram vial (topped with a Teflon-lined
cap) was charged with 2-methylhept-6-en-3-yl tosylcarbamate
(97.5 mg, 0.3 mmol, 1.0 equiv). The following solids were all first
weighed to wax paper then sequentially added to the vial:
phenylbenzoquinone (58.0 mg, 0.315 mmol, 1.05 equiv), 1,2-bis
(phenylsulfinyl)ethane (4.2 mg, 0.015 mmol, 0.05 equiv), Pd(OAc)2/
bis-sulfoxide catalyst 1 (15.1 mg, 0.03 mmol, 0.1 equiv), Teflon stir
bar. THF (0.45 mL, 0.66 M) was added, the vial was capped and
placed in a 45 ꢁC oil bath and stirred for 72 h. The reaction mixture
was transferred to a separatory funnel and diluted with CH2Cl2
(25 mL). Saturated NH4Cl (15 mL) and brine (15 mL) were added
and the aqueous and organic layers were separated. The aqueous
layer was extracted with CH2Cl2 (3ꢂ25 mL). The combined organic

4820
X.(Ben) Qi et al. / Tetrahedron 66 (2010) 4816e4826
layers were dried over MgSO4, filtered, and concentrated in vacuo.
A portion of the crude reaction mixture was analyzed by GC to
obtain the crude diastereoselectivity. After analysis, this sample
was added back to the total crude reaction mixture. Purification by
flash chromatography (1:1 hexanes/methylene chloride, gradient
1.0e2.5% acetone) provided a mixture of syn- and anti- 6-isopropyl-
3-tosyl-4-vinyl-1,3-oxazinan-2-one (6 mg, 0.02 mmol, 6% yield
[5.0:1 dr]).
(106.8 mg, 0.30 mmol, 1.0 equiv), Cr(III)(salen)Cl (11.4 mg,
0.018 mmol, 0.06 equiv), phenylbenzoquinone (110.5 mg, 0.6 mmol,
2 equiv), p-nitrobenzoic acid (5.1 mg, 0.03 mmol, 0.10 equiv), 1,2-bis
(phenylsulfinyl)ethane (4.2 mg, 0.015 mmol, 0.05 equiv), Pd(OAc)2/
1,2-bis(phenylsulfinyl)ethane catalyst
1
(15.1 mg, 0.03 mmol,
0.10 equiv), and a Teflon stir bar. In a separate flask, O2 gas was
simultaneously bubbled through 1,2-dichloroethane for thirty
minutes. The oxygenated 1,2-dichloroethane (0.66 M) was then
added to the previous one dram vial, O2 gas was blown over the vial
for 5 s, and the vial was sealed with a Teflon-lined cap. The reaction
vial was stirred in a 45 ꢁC oil bath for 1.5 h. The solution was allowed
to cool to room temperature and then transferred using dichloro-
methane (30 mL) to a 60 mL separatory funnel. The organic solution
was washed with satd aq NH4Cl solution (25 mL) and brine (30 mL).
The organic solution was dried over MgSO4, filtered, and concen-
trated in vacuo. The crude reaction mixture was checked by 1H NMR
to determine the dr and then purified using flash column chroma-
tography. Run 1 (92 mg, 0.26 mmol, 87% [4.2:1 dr]); run 2 (97 mg,
0.27 mmol, 91% [4.4:1 dr (syn/anti)]). Average yield: 89%, 4.3:1 dr
(syn/anti).
4.2.4. Table 1B entry 2. Following the procedureoutlinedinTable 1B,
entry 1, 2-methylhept-6-en-3-yl (4-nitrophenyl)sulfonylcarbamate
(106.8 mg,0.30 mmol,1.0 equiv)wasused. After24 hthereactionwas
quenched. The diastereoselectivity was obtained by 1H NMR analysis
of the crude reaction mixture. Purification by flash chromatography
(1:1 hexanes/methylene chloride, gradient 1.0e2.5% acetone) pro-
vided
a mixture of syn- and anti- 6-isopropyl-3-(4-nitro-
phenylsulfonyl)-4-vinyl-1,3-oxazinan-2-one (66 mg, 0.19 mmol, 62%
yield [4.1:1 dr]).
4.2.5. Table 1B entry 3. A one dram vial (topped with a Teflon-lined
cap) was charged with 2-methylhept-6-en-3-yl tosylcarbamate
(97.5 mg, 0.3 mmol, 1.0 equiv). The following solids were all first
weighed to wax paper then sequentially added to the vial: phe-
nylbenzoquinone (58.0 mg, 0.315 mmol, 1.05 equiv), 1,2-bis(phe-
nylsulfinyl)ethane (4.2 mg, 0.015 mmol, 0.05 equiv), Pd(OAc)2/bis-
sulfoxide catalyst 1 (15.1 mg, 0.03 mmol, 0.1 equiv), Cr(III)(salen)Cl
(11.4 mg, 0.018 mmol, 0.06 equiv), Teflon stir bar. THF (0.45 mL,
0.66 M) was added, the vial was capped and placed in a 45 ꢁC oil
bath and stirred for 5 h. The reaction mixture was transferred to
a separatory funnel and diluted with CH2Cl2 (25 mL). Saturated
NH4Cl (15 mL) and brine (15 mL) were added and the aqueous and
organic layers were separated. The aqueous layer was extracted
with CH2Cl2 (3ꢂ25 mL). The combined organic layers were dried
over MgSO4, filtered, and concentrated in vacuo. A portion of the
crude reaction mixture was analyzed by GC to obtain the crude
4.2.8. Table 1B entry 7. Following the procedure outlined in Table
1B, entry 6, 2-methylhept-6-en-3-yl (4-nitrophenyl)sulfo-
nylcarbamate (35.6 mg, 0.10 mmol, 1.0 equiv) and 2,5-dime-
thylbenzoquinone (27.2 mg, 0.20 mmol, 2.0 equiv) was used. The
yield and remaining starting material were determined through
1H NMR analysis using nitrobenzene (0.04 mmol) as an internal
standard. Run 1 (7% yield syn [anti product not observed by 1H
NMR due to low levels of product formation], 82% remaining
starting material); run 2 (10% yield syn [anti product not observed
by 1H NMR due to low levels of product formation], 80% remaining
starting material). Average yield: 8.5%; average remaining starting
material: 81%.
4.3. Preparation of starting materials
4.3.1. Preparation of tert-butyl ((2R,3R)-1-(tert-butyldimethylsilyl)-
2-formyl-4-oxoazetidin-3-yl)carbamate (þ)-19. A high pressure
vessel (100 mL) was sequentially charged with a stir bar, anhy-
drous ethanol (30 mL), (2R,3R)-methyl 3-(((benzyloxy)carbonyl)
amino)-4-oxoazetidine-2-carboxylate (synthesized in eight steps
including one chiral resolution)13 19-a (1.0 g, 3.59 mmol, 1 equiv)
and Boc2O (980 mg, 4.49 mmol, 1.25 equiv). The solution was
degassed with bubbling nitrogen for 10 min. Palladium catalyst
(300 mg, 10% on carbon) was added. The reaction was stirred
under 40 psi hydrogen for 3 h. The mixture was filtered through
Celite to remove the catalyst and the filtrate was concentrated to
a crude oil (827 mg).
The crude product was dissolved in anhydrous DMF (7 mL)
and the mixture was cooled to 0 ꢁC for 5 min. To this solution,
triethylamine (358 mg, 3.54 mmol, 1.05 equiv), TBSCl (676 mg,
4.4 mmol, 1.3 equiv) and DMAP (70 mg, 0.57 mmol, 0.17 equiv)
were added sequentially with exposure to air. The mixture was
diastereoselectivity. After analysis, this sample was added back to
the total crude reaction mixture. Purification by flash chromatog-
raphy provided a mixture of syn- and anti- 6-isopropyl-3-tosyl-4-
vinyl-1,3-oxazinan-2-one. Run 1: (78 mg, 0.24 mmol, 80% yield
[4.3:1 dr]); Run 2: (72 mg, 0.22 mmol, 74% yield [4.0:1 dr]). Average:
77% yield, 4.2:1 dr (syn/anti).
4.2.6. Table 1B entry 4. Following the procedureoutlinedinTable 1B,
entry 3, 2-methylhept-6-en-3-yl (4-nitrophenyl)sulfonylcarbamate
(106.8 mg, 0.30 mmol, 1.0 equiv) was used. After 2.5 h the reaction
was quenched. The diastereoselectivity was obtained by 1H NMR
analysis of the crude reaction mixture. Run 1 (92 mg, 0.26 mmol, 87%
yield [2.9:1 dr]); Run 2: (92 mg, 0.26 mmol, 87% yield [2.8:1 dr]).
Average: 87% yield, 2.9:1 dr (syn/anti).
4.2.7. Table 1B entry 6. In a one dram vial was added 2-methylhept-
6-en-3-yl (4-nitrophenyl)sulfonylcarbamate starting material

X.(Ben) Qi et al. / Tetrahedron 66 (2010) 4816e4826
4821
stirred at 0 ꢁC for 15 min and warmed to rt over 2e3 h. Yellow
precipitate was formed during the reaction. The solid was fil-
tered off and washed by ethyl acetate for three times. The or-
ganic solution was extracted with water (2ꢂ50 mL) and brine
(2ꢂ50 mL). The organic layer was dried and concentrated to
a residue of clear oil, which was dried under vacuum overnight
to give the crude product 19-c (905 mg, 74.6%). The above
crude product was dissolved in ether and filtered over a short
plug of silica gel and then concentrated to a residue of white
solid.
yielding a light yellow solid. The yellow solid was stored under
Argon atmosphere at ꢀ20 ꢁC.
4.3.3. tert-Butyl-((2R,3R)-1-(tert-butyldimethylsilyl)-2-(1-hydrox-
ybut-3-en-1-yl)-4-oxoazetidin-3-yl)carbamate.
OH
BocHN
NTBS
O
The crude solid was dissolved in anhydrous THF (10 mL) and the
solution was cooled to 0 ꢁC for 5 min. LiBH4 (246 mg, 11.3 mmol,
3.84 equiv) was added to the reaction slowly with exposure to air.
The resulting mixture was stirred at 0 ꢁC for 4 h and added drop-
wise (CAUTION!) a solution of AcOH (2.5 mL) in ethyl acetate
(10 mL) at 0 ꢁC. Saturated NaHCO3 solution was added to the re-
action mixture slowly (CAUTION!) until no gas was bubbled. The
resulting solution was extracted with ethyl acetate (100 mL) and
separated. The organic solution was washed with brine (2ꢂ60 mL),
dried over Na2SO4, and concentrated to a residue of white solid
(633 mg, 76%).
A flame-dried 25 mL round bottom flask was sequentially
charged with a stir bar, dichloromethane (4 mL) and DMSO
(0.21 mL, 2.97 mmol, 2.7 equiv). To the mixture was added
dropwise (over 5 min) at ꢀ78 ꢁC a solution of oxalyl chloride
(0.125 mL, 1.43 mmol, 1.3 equiv) in DCM (4 mL). A solution of
starting alcohol tert-butyl ((2R,3R)-1-(tert-butyldimethylsilyl)-2-
(hydroxymethyl)-4-oxoazetidin-3-yl)carbamate 19-d (363 mg,
1.1 mmol, 1 equiv) in DCM (4 mL) was added over a period of
5 min. This was followed by dropwise addition of a solution of
triethylamine (0.46 mL, 3.3 mmol, 3 equiv) in DCM (2 mL). The
resulting mixture was stirred at ꢀ78 ꢁC for 5 min and the cold
bath was removed. The reaction was warmed to room tempera-
ture and stirred at rt for 15 min. The reaction solution was diluted
with 100 mL of DCM and washed with 100 mL water, then with
10% KHSO4 solution. The organic solution was dried and con-
centrated to a residue of crude aldehyde, which was purified by
flash chromatography on silica gel (5%e20% EtOAc/hexanes) to
give the title compound (þ)-19 (342.0 mg, 95%) as a white solid;
1H NMR (500 MHz, CDC13) 9.72 (1H, s, CHO), 5.15e5.14 (1H, m,
NH), 5.09e5.06 (1H, m, BocNCH), 4.32 (1H, d, J¼5.5 Hz, CHNTBS),
1.40 (9H, s, Boc), 0.96 (9H, s, TBS), 0.33 (3H, s, TBS), 0.15 (3H, s,
TBS); 13C NMR (125 MHz, CDCl3) 199.3, 171.2, 154.9, 81.0, 62.9,
62.3, 28.2, 26.2, 18.6, ꢀ5.5, ꢀ5.6; IR (film, cmꢀ1):3400e3100 (br),
2956, 2931, 2860, 1759, 1720, 1518, 1471, 1367, 1253, 1167, 1060,
The above aldehyde was dissolved in dry THF (10 mL) and
cooled to ꢀ40 ꢁC (MeCN/CO2). To this mixture was added dropwise
a solution of allylMgBr (1.69 mL, 0.78 M in ether, 1.2 equiv) in THF
(5 mL). After addition, the resulting mixture was stirred at ꢀ40 ꢁC
for 3 h. TLC showed no aldehyde left. The reaction was quenched by
satd aq NH4Cl solution (25 mL) and diluted with ether (30 mL). The
organic solution was dried over MgSO4 and concentrated. The
crude product was purified by flash chromatography on silica gel
(5e20% EtOAc/hexanes), and evaporated to dryness (300 mg mix-
ture of two diastereomers, dr¼1.2:1, 74% yield). 1H NMR (500 MHz,
CDC13) of mixture: 5.87e5.76 (2H, m, 2ꢂCH]CH2), 5.66 (1H, d,
J¼10.5 Hz, NH), 5.42 (1H, d, J¼9.5 Hz, NH), 5.26e5.14 (6H, m),
4.03e4.00 (1H, m, CHOH), 3.75e3.73 (2H, m, 2ꢂTBSNCH),
3.69e3.65 (1H, m, CHOH), 2.36e2.30 (2H, m, CH2CHCH2CHOH),
2.28e2.19 (2H, m, CH2CHCH2CHOH), 2.01 (1H, s, OH), 1.78 (1H, d,
J¼6.5 Hz, OH), 1.44 (9H, s, Boc), 1.43 (9H, s, Boc), 0.99 (9H, s, TBS),
0.969 (9H, s, TBS), 0.27 (3H, s, TBS), 0.26 (3H, s, TBS), 0.24 (3H, s,
TBS), 0.22 (3H, s, TBS); 13C NMR (500 MHz, CDCl3) of mixture: one
diastereomer:174.5, 155.3, 133.9, 119.1, 80.4, 69.8, 60.0, 59.2, 39.6,
28.4, 26.3, 19.0, ꢀ4.8, ꢀ5.3; another diastereomer: 174.3, 155.0,
133.9,119.0, 80.1, 70.8, 59.2, 58.8, 37.7, 28.3, 26.2,18.6, ꢀ4.8, ꢀ5.4; IR
(film, cmꢀ1): 2956, 2929, 2860, 1731, 1697, 1512, 1367, 1254, 1167,
1063, 841, 825, 785; HRMS (ESI) m/z calcd for C18H35N2O4Si
[MþH]þ: 371.2366, found 371.2373.
4.3.4. (ꢀ)-tert-Butyl-((2R,3R)-1-(tert-butyldimethylsilyl)-2-((R)-1-
((((4-nitrophenyl)sulfonyl)carbamoyl)oxy)but-3-en-1-yl)-4-ox-
oazetidin-3-yl)carbamate (ꢀ)-7.
O
O
y
NHNs
BocHN
O
x
NTBS
(-)-7
1032, 1009, 841, 823, 783,679; HRMS (ESI) m/z calcd for
25
C15H29N2O4Si [MþH]þ: 329.1897, found 329.1893; [
a
]
þ22.4 (c
A flame-dried 250 mL round bottom flask was charged sequen-
tially with a stir bar, the homoallylic alcohol mixture of two di-
astereomers starting material (320 mg, 0.86 mmol, 1 equiv) and
tetrahydrofuran (1 mL). The flask was cooled to 0 ꢁC followed by the
rapid addition of solid p-nitrobenzenesulfonyl isocyanate (NsNCO
[for procedure of NsNCO synthesis see below], 217 mg, 0.95 mmol,
1.1 equiv). The solution was stirred for 30 min and then quenched by
diluting with saturated ammonium chloride. The organic layer was
washed once with brine then dried over MgSO4, filtered, and con-
centrated in vacuo. Purification by flash chromatography (15e40%
EtOAc/hexanes, 1% AcOH) provided the two diastereomers (468 mg,
91% total yield). Further purification by flash chromatography
(10e30% gradient EtOAc/hexanes, 0.5% AcOH) provided one pure
diastereomer, tert-butyl ((2R,3R)-1-(tert-butyldimethylsilyl)-2-((R)-
D
1.0, CHCl3).
4.3.2. Procedure for the synthesis of p-nitrobenzenesulfonyl iso-
cyanate (NsNCO). A flame-dried 100 mL three-neck flask was
equipped with a cold-finger, glass stopper and a stopcock joint
(the stopcock valve is kept closed). 4-Nitrobenzenesulfonamide
(1.82 g, 9 mmol, 1.0 equiv), butyl isocyanate (400 mL, 3.6 mmol,
0.40 equiv), and 1,2-dichlorobenzene (14 mL) were added and
taken to reflux. Upon the solution turning clear, the phosgene
generation cartridge (20 mmol, 2.2 equiv, Aldrich) was connected
to the stopcock and the stopcock valve was opened. The phosgene
cartridge was heated to 100 ꢁC in a separate oil bath while keeping
the three-neck flask at reflux. After complete evolution of the
phosgene (1 h) the cartridge was removed and quenched with
absolute ethanol. The reaction flask was allowed to cool to room
temperature and nitrogen gas was blown over the reaction flask
for two hours. The 1,2-dichlorobenzene was then distilled away
(1.0 Torr, 80 ꢁC) and the remaining dark brown oil was transferred
to a Kugelrohr distillation flask and distilled (1.0 Torr, 170 ꢁC)
1-((((4-nitrophenyl)sulfonyl)
carbamoyl)oxy)but-3-en-1-yl)-4-
oxoazetidin-3-yl)carbamate 8 as white solid (210 mg, 0.38 mmol,
44% yield).1H NMR (500 MHz, CD3OD) 8.43 (2H, d, J¼9.0 Hz, Ns), 8.22
(2H, d, J¼9.0 Hz, Ns), 7.81 (1H, d, J¼9.0 Hz, BocNHCH), 5.59 (1H, m,
CH]CH2), 5.02e4.99 (1H, m, BocNHCH), 4.95e4.88 (2H, m,
CH]CH2), 4.74 (1H, brd, J¼10.0 Hz, CH2]CHCH2CHOCONHNs), 3.86

4822
X.(Ben) Qi et al. / Tetrahedron 66 (2010) 4816e4826
(1H, dd, J¼10.0, 5.8 Hz, NTBSCH), 2.27 (1H, brd, J¼13.5 Hz, CH2]
CHCH2CHOCONHNs), 2.09 (1H, p, J¼7.6, Hz CH2]CHCH2CHO-
CONHNs),1.41 (9H, s, Boc), 0.85 (9H, s, TBS), 0.17 (3H, s, TBS), 0.15 (3H,
s, TBS); 13C NMR (125 MHz, CDCl3) 173.9, 155.3, 150.7, 150.1, 144.0,
131.8, 129.8, 124.2, 119.1, 81.0, 75.8, 59.4, 57.6, 36.0, 28.2, 26.3, 18.8,
ꢀ5.0, ꢀ5.2; IR (film, cmꢀ1):3500e3300 (br), 3109, 3084, 2958, 2931,
2860, 1751, 1728, 1535, 1456, 1367, 1350, 1253, 1223, 1161, 1090, 1061,
1014, 899, 843, 825, 737, 607; HRMS (ESI) m/z calcd for C25H39N4O9SiS
(5 mL) to keep a slow reflux. The resulting mixture was stirred at rt
for 30 min and the cold bath (ꢀ40 ꢁC/MeCN/CO2) was applied. The
aldehyde tert-butyl ((2R,3R)-1-(tert-butyldimethylsilyl)-2-formyl-
4-oxoazetidin-3-yl)carbamate 2 was dissolved in dry THF (5 mL)
and added dropwise to the solution of butenylMgBr in ether. (Pre-
cipitation was observed during addition, warming to 0 ꢁC was
helpful to avoid the precipitation). After addition, the resulting
mixture was stirred at ꢀ35 ꢁC for 3 h. TLC showed no aldehyde was
left. The reaction was quenched by satd aq NH4Cl solution (25 mL)
and diluted with ether (30 mL). The organic solution was dried over
MgSO4 and concentrated. The crude product was purified by flash
chromatography on silica gel (5e20% EtOAc/hexanes), and evapo-
rated to provide white solid (0.86 g of a diastereomer mixture was
isolated (dr¼7:1, anti/syn), 70% yield). The major anti-isomer, 1H
NMR (500 MHz, CD3OD) 5.83 (1H, ddt, J¼16.5, 10.0, 6.8 Hz, CH]
CH2), 5.08 (1H, d, J¼5.5 Hz, BocNHCH), 5.06 (1H, dd, J¼16.5, 1.0 Hz,
CH]CH2), 4.97 (1H, d, J¼10.5 Hz, CH]CH2), 3.97e3.95 (1H, m,
CHOH), 3.83 (1H, dd, J¼5.5, 1.3 Hz, TBSNCH), 2.29e2.21 (1H, m,
CH2]CHCH2CH2CHOH), 2.16e2.08 (1H, m, CH2]CHCH2CH2CHOH),
1.61e1.51 (2H, m, CH2]CHCH2CH2CHOH),1.44 (9H, s, Boc), 0.97 (9H,
s, TBS), 0.29 (3H, s, TBS), 0.22 (3H, s, TBS); 13C NMR (125 MHz, CDCl3)
174.6, 155.1, 137.7, 115.6, 80.1, 71.2, 59.4, 59.2, 31.7, 30.5, 28.4, 26.3,
18.7, ꢀ5.1, ꢀ5.0; IR (film, cmꢀ1):2931, 2891, 2860, 1730, 1687, 1423,
1365,1338,1254,1176,1078, 841, 825, 785; HRMS (ESI) m/z calcd for
C19H37N2O4Si [MþH]þ: 385.2523, found 385.2499.
[MþH]þ: 599.2207, found 599.2212; [
a]
D
25 ꢀ40.0 (c 1.0, CHCl3).
The syn/anti configuration of Cx and Cy in this diastereomer 7
can be determined by comparison of their 1H NMR data with that
reported in the literature for related compounds.14 In this way, the
vicinal coupling constant between Hx and Hy is larger for syn-iso-
mers (5.3e7.8 Hz) than for anti-isomers (2.4e5.9 Hz). For substrate
7, 3JHxHy of the syn-isomers 7 is 6.0 Hz, which is assigned to be the
3
syn-isomers. The anti-isomer 7 showed a JHxHy of 0.0 Hz (see
spectrum). More detailed discussion about the configuration as-
signments for b
-lactams can be found in the literature.15
4.3.5. 1-((2R,3R)-3-((tert-Butoxycarbonyl)amino)-1-(tert-butyldime-
thylsilyl)-4-oxoazetidin-2-yl)but-3-en-1-yl acetate 11.
OAc
BocHN
N
TBS
O
11
4.3.7. (ꢀ)-tert-Butyl-((2R,3R)-1-(tert-butyldimethylsilyl)-2-((R)-1-
((((4-nitrophenyl)sulfonyl)carbamoyl)oxy)pent-4-en-1-yl)-4-
oxoazetidin-3-yl)carbamate (ꢀ)-9.
To a flame-dried 15 mL flask with Teflon stir bar was sequentially
charged with homoallylic alcohol 7 (194 mg, 0.524 mmol,1.0 equiv),
DMAP (12.8 mg, 0.15 mol, 0.2 equiv), and DCM (6 mL) then cooled to
0 ꢁC. Triethylamine (0.73 mL, 5.24 mmol, 10 equiv) and Ac2O
(0.2 mL, 2.1 mmol, 4 equiv) were added dropwise. After the addition
was completed, the reaction slowly warmed to room temperature
over 4 h. TLC (30% EA/Hexanes, Rf w0.5, stained by K2MnO4) showed
full conversion. The reaction was quenched by satd aq NH4Cl solu-
tion (10 mL) and diluted with ether (20 mL). The organic solution
was dried over MgSO4 and concentrated. The crude product was
purified by flash chromatography on silica gel (5% to 20% EtOAc/
hexanes), and evaporated to a white solid (183 mg mixture of two
diastereomers, 85% yield). 1H NMR (500 MHz, CDC13) of mixture:
5.76e5.66 (2H, m, 2ꢂCHCH2), 5.36e5.28 (3H, m), 5.17e5.07 (4H, m),
4.93e4.88 (1H, m, CHOAc), 3.87e3.82 (2H, m, 2ꢂTBSNCH),
2.49e2.36 (2H, m, CH2]CHCH2CHOAc), 2.32e2.19 (2H, m, CH2]
CHCH2CHOAc), 2.10 (3H, s, OCOCH3), 2.07 (3H, s, OCOCH3), 1.46 (9H,
s, Boc),1.43 (9H, s, Boc), 0.94 (9H, s, TBS), 0.91 (9H, s, TBS), 0.24 (6H, s,
TBS), 0.22 (3H, s, TBS), 0.18 (3H, s, TBS); 13C NMR (125 MHz, CDCl3)
one diastereomer: 173.7, 170.1, 155.0, 132.5, 118.7, 80.1, 73.2, 59.3,
57.4, 35.7, 28.2, 26.3, 21.4, 18.9, ꢀ5.2, ꢀ5.6; another diastereomer:
173.0, 170.0, 154.7, 132.4, 118.5, 80.1, 71.7, 59.0, 57.3, 35.2, 28.1, 26.1,
20.9, 18.6, ꢀ5.4, ꢀ6.1; IR (film, cmꢀ1):3500e3100 (br), 2958, 2931,
2899, 2860,1743,1716,1529,1471,1392,1367,1252,1232,1167,1061,
1022, 918, 841, 825, 785, 681; HRMS (ESI) m/z calcd for C20H37N2O5Si
[MþH]þ: 413.2472, found 413.2480.
O
O
y
NHNs
BocHN
O
x
NTBS
9
(-)-
A flame-dried 250 mL round bottom flask was charged se-
quentially with a stir bar, the homoallylic alcohol, tert-butyl
((2R,3R)-1-(tert-butyldimethylsilyl)-2-((R)-1-hydroxypent-4-en-1-
yl)-4-oxoazetidin-3-yl)carbamate (192 mg, 0.5 mmol, 1 equiv) and
tetrahydrofuran (3 mL). The flask was taken to 0 ꢁC followed by
the rapid addition of solid p-nitrobenzenesulfonyl isocyanate
(NsNCO, 125 mg, 0.55 mmol, 1.1 equiv). The solution was stirred for
30 min and then quenched by diluting with saturated ammonium
chloride. The organic layer was washed once with brine then dried
over MgSO4, filtered, and concentrated in vacuo. Purification by
flash chromatography (15e40% EtOAc/hexanes, 1% AcOH) provided
two diastereomers of bishomoallylic N-nosyl carbamates 9.
(270 mg, white solid, 88% total yield). Further purification by flash
chromatography (10e30% gradient EtOAc/hexanes/0.5% AcOH)
provided one pure diastereomer, tert-butyl-((2R,3R)-1-(tert-
butyldimethylsilyl)-2-((R)-1-((((4-nitrophenyl)sulfonyl)carba-
moyl)oxy)pent-4-en-1-yl)-4-oxoazetidin-3-yl)carbamate (ꢀ)-9
as white solid (236 mg, 77% yield). 1H NMR (500 MHz, CD3OD) 8.45
(2H, d, J¼9.0 Hz, Ns), 8.25 (2H, d, J¼9.0 Hz, Ns), 6.82 (1H, d,
J¼10.5 Hz, BocNHCH), 5.70e5.62 (1H, m, CH]CH2), 5.20 (1H, dd,
J¼10.0, 5.5 Hz, BocNHCH), 5.14 (1H, app. t, J¼6.5 Hz, CHOCO),
4.91e4.89 (2H, m, CH]CH2), 3.96 (1H, dd, J¼5.5, 1.5 Hz, NTBSCH),
1.98e1.88 (2H, m, CH2]CHCH2CH2), 1.62 (2H, app. q, J¼7.5 Hz,
CH2]CHCH2CH2), 1.48 (9H, s, Boc), 0.84 (9H, s, TBS), 0.13 (3H, s,
TBS), ꢀ0.07 (3H, s, TBS); 13C NMR (125 MHz, MeOH-d4) 175.8, 157.0,
152.3, 152.0, 146.0, 138.0, 130.8, 125.5, 116.1, 81.5, 76.0, 59.9, 59.8,
30.8, 30.6, 28.7, 26.7, 20.0, ꢀ5.5, ꢀ6.2; IR (film, cmꢀ1): 3500e3200
(br), 2958, 2931, 2883, 2858, 1757, 1714, 1535, 1456, 1394, 1352, 1311,
1280, 1253, 1224, 1165, 1090, 1060, 1029, 1012, 920, 843, 825, 789,
768, 739, 683, 609, 565; HRMS (ESI) m/z calcd for HRMS (ESI) m/z
4.3.6. tert-Butyl-((2R,3R)-1-(tert-butyldimethylsilyl)-2-((R)-1-hy-
droxypent-4-en-1-yl)-4-oxoazetidin-3-yl)carbamate.
OH
BocHN
NTBS
O
A flame-dried 50 mL round bottom flask was sequentially
charged with a stir bar, Mg (432 mg, 18 mmol, 6 equiv), I2 (30 mg,
0.12 mmol, 0.01 equiv), and ether (20 mL). Tothe mixturewas added
dropwise 4-bromobut-1-ene (0.914 mL, 9 mmol, 3 equiv) in ether

X.(Ben) Qi et al. / Tetrahedron 66 (2010) 4816e4826
4823
27
calcd for C26H40N4O9SSi [MþH]þ: 613.2364, found 613.2385. [
ꢀ12.8 (c 1.0, MeOH).
a]
D
following solids were all first weighed to wax paper then
sequentially added to the vial: Pd(OAc)2/bis-sulfoxide catalyst 1
Configuration of the diastereomer was confirmed by the 1H
NMR data of coupling constant of JHxHy, the vicinal coupling con-
(5.02 mg,
0.01 mmol,
0.1 equiv),1,2-bis(phenylsulfinyl)ethane
3
(1.4 mg, 0.005 mmol, 0.05 equiv), phenylbenzoquinone (19.3 mg,
0.105 mmol, 1.05 equiv), and Cr(III)(salen)Cl (3.8 mg, 0.006 mmol,
0.06 equiv).The reaction was finally charged with a stir bar and
allowed to stir at 45 ꢁC. After 72 h the reaction mixture was
transferred to a separatory funnel and diluted with ether (25 mL).
K2CO3 (5%) was added and the organic solution was washed by
K2CO3 (5%) three times. The aqueous and organic layers were
separated. The aqueous layer was extracted with ether (3ꢂ25 mL).
The combined organic layers were dried over MgSO4, filtered, and
concentrated in vacuo. The diastereoselectivity was obtained by 1H
NMR analysis of the crude reaction mixture. The crude reaction
mixture was purified using flash column chromatography to pro-
vide a white solid. Run 1 (45 mg, 0.076 mmol, 76% [>20:1 dr]); run
2 (45 mg, 0.076 mmol, 76% [>20:1 dr]). Average yield: 76%, >20:1 dr
(anti/syn). 1H NMR (500 MHz, CDC13) 8.39 (2H, d, J¼9.0 Hz, Ns),
8.25 (2H, d, J¼8.5 Hz, Ns), 5.73e5.66 (1H, m, CH]CH2), 5.50 (1H, d,
J¼17.0 Hz, CH]CH2), 5.44 (1H, d, J¼10.0 Hz, CH]CH2), 5.08e5.11
(2H, m, BocNHCH, and BocNHCH), 4.77 (1H, br d, J¼8.0 Hz,
OCHCHNNs), 4.28 (1H, d, J¼9.5 Hz, OCHCHNNs), 3.81e3.78 (1H, m,
TBSNCH), 1.45 (9H, s, Boc), 0.93 (9H, s, TBS), 0.24 (3H, s, TBS), 0.23
(3H, s, TBS); 13C NMR (125 MHz, CDCl3) 171.8, 155.4, 151.1, 150.3,
143.3, 131.6, 130.3, 124.4, 122.1, 81.7, 81.6, 61.5, 59.8, 57.9, 28.4, 26.5,
18.7, ꢀ5.2, ꢀ5.4; IR (film, cmꢀ1): 2962, 2931, 2899, 2860, 1792, 1759,
1743, 1716, 1535, 1383, 1367, 1350, 1254, 1182, 1120, 1061, 1012, 845,
stant between Hx and Hy is larger for syn-isomers than for anti-
isomers. For substrate 9, 3JHxHy of anti-isomer 9 is 1.5 Hz, but 3JHxHy
of syn-isomers 9 is 5.5 Hz. (see spectrum).14
4.3.8. (ꢀ)-(S)-1-((2R,3R)-3-((tert-Butoxycarbonyl)amino)-1-(tert-
butyldimethylsilyl)-4-oxoazetidin-2-yl)pent-4-en-1-yl acetate (ꢀ)-13.
OAc
BocHN
x
y
n=2
N
TBS
(-)-13
O
To a flame-dried 15 mL flask with Teflon stir bar was sequen-
tially charged with bis-homoallylic alcohol tert-butyl ((2R,3R)-1-
(tert-butyldimethylsilyl)-2-((R)-1-hydroxypent-4-en-1-yl)-4-oxoa-
zetidin-3-yl)carbamate (192 mg, 0.5 mmol, 1.0 equiv), DMAP
(10 mg), and DCM (6 mL) then cooled to 0 ꢁC. Triethylamine
(0.7 mL, 5 mmol, 10 equiv) and Ac2O (0.19 mL, 2 mmol, 4 equiv)
were added dropwise. After the addition was completed, the re-
action mixture was slowly warmed to room temperature over 4 h.
TLC (30 % EA/Hexanes, Rf w0.5, stained by K2MnO4) showed full
conversion. The reaction was quenched by satd aq NH4Cl solution
(10 mL) and diluted with ether (20 mL). The organic solution was
dried over MgSO4 and concentrated. The crude product was puri-
fied by flash chromatography on silica gel (5e20% EtOAc/hexanes),
and evaporated to dryness (185 mg, 87% yield). White solid, 1H
NMR (500 MHz, CDC13) 5.76 (1H, ddt, J¼17.0, 10.0, 6.5 Hz,
CH]CH2), 5.35e5.25 (3H, m, BocNHCH and CHOAc), 5.06e5.00
(2H, m, CH]CH2), 3.82 (1H, dd, J¼5.5, 1.8 Hz, TBSNCH), 2.14e2.08
(2H, m, CH2]CHCH2CH2CHOAc), 2.11 (3H, s, OCOCH3), 1.79e1.71
(1H, m, CH2]CHCH2CH2CHOAc), 1.64e1.58 (1H, m, CH2]
CHCH2CH2CHOAc), 1.43 (9H, s, Boc), 0.96 (9H, s, TBS), 0.28 (3H, s,
TBS), 0.20 (3H, s, TBS); 13C NMR (125 MHz, CDCl3) 173.9,170.1,154.7,
136.9, 115.7, 80.4, 72.5, 59.1, 58.2, 30.1, 29.8, 28.3, 26.2, 21.1, 19.2,
ꢀ5.4, ꢀ6.1; IR (film, cmꢀ1): 3400e3100 (br), 3074, 2954, 2931,
2902, 2860, 1739, 1714, 1535, 1471, 1367, 1305, 1290, 1252, 1234,
825, 739, 683, 617; HRMS (ESI) m/z calcd for C25H37N4O9SiS
20
[MþH]þ: 597.2051, found 597.2056;[
a]
ꢀ24.8 (c 0.5, CHCl3).
D
The same reaction was set up without Cr(III)(salen)Cl providing
the same product with full conversion. Run 1 (25 mg, 0.042 mmol,
42% [>20:1 dr]); run 2 (30 mg, 0.050 mmol, 50% [>20:1 dr]).
Average yield: 46%, >20:1 dr (anti/syn).
4.4.2. (þ)-tert-Butyl-((2R,3R)-1-(tert-butyldimethylsilyl)-2-((4S,6R)-
3-((4-nitrophenyl)sulfonyl)-2-oxo-4-vinyl-1,3-oxazinan-6-yl)-4-
oxoazetidin- 3-yl)carbamate (þ)-10.
O
O
y
NNs
c
BocHN
O
z
x
1172, 1061, 1026, 843, 825, 787; HRMS (ESI) m/z calcd for
25
C21H39N2O5Si [MþH]þ: 427.2628, found 427.2626; [
a
]
ꢀ10.9 (c
Hb Ha
TBS
N
D
1.0, CHCl3).
(+)-10
The syn/anti configuration of C4 and C5 in this diastereomer 13
can be determined by comparison of their 1H NMR data with that
reported in the literature for related compounds. In this way, the
vicinal coupling constant between Hx and Hy is larger for syn-iso-
mers than for anti-isomers. For substrate 13, 3JHxHy of anti-isomers
13 is 1.8 Hz, but 3JHxHy of syn-isomers 13 is 5.5 Hz.14
In a one dram vial was added the tert-butyl ((2R,3R)-1-(tert
butyldimethylsilyl)-2-((R)-1-((((4-nitrophenyl)sulfonyl)carbamoyl)
oxy)pent-4-en-1-yl)-4-oxoazetidin-3-yl)carbamate starting mate-
rial (ꢀ)-9 (61 mg, 0.1 mmol, 1 equiv), phenylbenzoquinone (37 mg,
0.2 mmol, 2 equiv), p-nitrobenzoic acid (1.7 mg, 0.01 mmol,
0.10 equiv), 1,2-bis(phenylsulfinyl)ethane (1.4 mg, 0.005 mmol,
4.4. General procedure for Table 2
0.05 equiv), Pd(OAc)2/1,2-bis(phenylsulfinyl)ethane catalyst
1
(5.02 mg, 0.001 mmol, 0.10 equiv), and a Teflon stir bar. In a sepa-
rate flask, O2 gas was simultaneously bubbled through 1,2-di-
chloroethane for 30 min. The oxygenated 1,2-dichloroethane
(0.66 M) was then added to the previous one dram vial, O2 gas was
blown over the vial for 5 s, and the vial was sealed with a Teflon-
lined cap. The reaction vial was stirred in a 45 ꢁC oil bath for 24 h.
The solution was allowed to cool to room temperature and then
transferred using dichloromethane (30 mL) to a 60 mL separatory
funnel. The organic solution was washed with satd aq NH4Cl so-
lution (25 mL) and brine (30 mL). The organic solution was dried
over MgSO4, filtered, and concentrated in vacuo. The crude reaction
mixture was checked by 1H NMR to determine the dr and then
purified using flash column chromatography. Run 1 (43 mg,
0.071 mmol, 71% [5.7:1 dr (syn/anti), relative to Hy and Hc]); run 2
4.4.1. (ꢀ)-tert-Butyl-((2R,3R)-1-(tert-butyldimethylsilyl)-2-((4S,5S)-
3-((4-nitrophenyl)sulfonyl)-2-oxo-4-vinyloxazolidin-5-yl)-4-
oxoazetidin-3-yl)carbamate (ꢀ)-8.
O
O
NNs
BocHN
O
NTBS
8
(-)-
A half dram vial (topped with a Teflon-lined cap) was charged
with the homoallylic N-nosyl carbamate substrate (ꢀ)-7
(0.10 mmol, 59.8 mg, 1.0 equiv) and THF (0.15 mL, 0.66 M). The

4824
X.(Ben) Qi et al. / Tetrahedron 66 (2010) 4816e4826
(49 mg, 0.081 mmol, 81% [5.9:1 dr (syn/anti)]). Average yield: 76%,
5.8:1 dr (syn/anti). The major syn-diastereoisomer can be isolated
by flash chromatography (15e50% gradient EtOAc/hexanes) di-
rectly from the crude reaction mixture. White solid, 1H NMR
(500 MHz, CDC13) 8.36 (2H, d, J¼9.0 Hz, Ns), 8.29 (2H, d, J¼9.0 Hz,
Ns), 5.51e5.44 (1H, m, CH]CH2), 5.36 (1H, d, J¼17.0 Hz, CH]CH2),
5.30e5.25 (2H, m, CH]CH2, and BocNHCH), 5.11 (1H, d, J¼9.0 Hz,
BocNHCH), 5.06 (1H, app. q, J¼8.5 Hz, CH2]CHCHNNs), 4.55 (1H,
app. dt, J¼12.0, 2.0 Hz, TBSNCHCHOCONNs), 3.85 (1H, dd, J¼5.5,
2.0 Hz, TBSNCH), 2.43e2.39 (1H, m, CH2CHCH]CH2), 1.91 (1H, ddd,
J¼14.0, 12.0, 8.5 Hz, CH2CHCH]CH2), 1.40 (9H, s, Boc), 0.94 (9H, s,
TBS), 0.27 (3H, s, TBS), 0.23 (3H, s, TBS); 13C NMR (125 MHz, CDCl3)
171.7, 154.9, 150.9, 149.7, 143.9, 136.0, 131.3, 123.9, 120.0, 81.1, 75.9,
59.7, 58.7, 56.6, 31.9, 28.4, 26.1, 18.7, ꢀ5.0, ꢀ5.3; IR (film,
cmꢀ1):2960, 2931, 2891, 2860, 1749, 1716, 1533, 1510, 1473, 1392,
unchanged relative to the starting material diastereomeric ratio.)
1H NMR (500 MHz, CDC13) of mixture: 7.66e7.64 (4H, m, 2ꢂTseH),
7.33e7.31 (6H, m, 2ꢂPheH), 7.20e7.15 (8H, m, PheH and TseH),
5.88e5.83 (3H, m), 5.74e5.70 (2H, m), 5.50e5.46 (2H, m), 5.30 (4H,
s), 5.14e5.09 (5H, m), 4.48e4.44 (4H, m), 3.89 (1H, t, J¼5.5 Hz), 3.84
(1H, br s), 2.40 (6H, s, TseCH3), 2.13 (3H, s, OCOCH3), 2.09 (3H, s,
OCOCH3), 1.46 (9H, s, Boc), 1.44 (9H, s, Boc), 0.96 (9H, s, TBS), 0.94
(9H, s, TBS), 0.30 (3H, s, TBS), 0.28 (3H, s, TBS), 0.23 (3H, s, TBS), 0.21
(3H, s, TBS); 13C NMR (125 MHz, CDCl3) one diastereomer: 173.7,
169.6, 154.7, 152.0, 144.7, 136.3, 134.5, 130.8, 129.4, 128.7, 128.6,
128.5, 128.3, 128.0, 80.7, 72.6, 69.3, 59.3, 58.7, 47.59, 28.4, 26.3, 21.7,
21.3, 19.1, ꢀ5.3, ꢀ5.7; another diastereomer: 172.8, 169.9, 154.9,
152.2, 144.7, 136.4, 134.5, 130.8, 129.4, 128.7, 128.6, 128.4, 128.3,
128.0, 80.2, 72.2, 69.5, 60.1, 57.7, 48.4, 28.4, 26.4, 21.7, 21.3, 18.9,
ꢀ5.3, ꢀ5.7; IR (film, cmꢀ1):2958, 2931, 2891, 2860,1739,1523,1456,
1365, 1267, 1253, 1230, 1171, 1088, 1059, 1020, 841, 825, 814, 785,
739, 700, 673, 594, 548; HRMS (ESI) m/z calcd for C35H50N3O9SiS
[MþH]þ: 716.3037, found 716.3024.
1367, 1352, 1254, 1178, 842, 825, 742, 611; HRMS (ESI) m/z calcd
26
for C26H38N4O9SiSNa [MþNa]þ: 633.2026, found 633.2015;[
þ5.4 (c 0.25, CHCl3).
a]
D
The stereochemistry of the syn- and anti-diastereomers of
oxazinanone was determined through their vicinal coupling con-
stants (3JHzHc). In general, syn-oxazinanones show a coupling con-
stant between CzHa and CzHb with CcH within 7.5e8.0 Hz and
9.5e10.5 Hz, and the anti-oxazinanones show a coupling constant
within 2.5e3.5 Hz and 4.5e5.5 Hz, respectively. The title oxazina-
none (þ)-10 showed the coupling constant is 8.5 Hz, which is
assigned to be the syn-diastereomer. Ref. 4e provides a more de-
tailed description of the relative data.
The same reaction was set up with Cr(III)(salen)Cl (3.8 mg,
0.006 mmol, 0.06 equiv) as the only additive providing the same
product with full conversion in 6 h. Run 1 (49 mg, 0.081 mmol, 81%
[2.9:1 dr (syn/anti), relative to Hy and Hc]); run 2 (49 mg,
0.081 mmol, 81% [3.3:1 dr (syn/anti)]). Average yield: 81%, 3.1:1 dr
(syn/anti).
4.5.2. (þ)-(1S,E)-5-(N-((Benzyloxy)carbonyl)-4-methyl-
phenylsulfonamido)-1-((2R)-3-((tert-butoxycarbonyl)amino)-1-
(tert-butyldimethylsilyl)-4-oxoazetidin-2-yl)pent-3-en-1-yl acetate
(þ)-14.
CBz
OAc
N Ts
BocHN
O
N
TBS
(+)-14
A one dram vial was charged with bis-homoallylic acetate
(ꢀ)-13 (42.6 mg, 0.1 mmol,1.0 equiv), followed by tert-butyl methyl
ether (0.15 mL). 1,2-Bis(phenylsulfinyl)ethane palladium(II) acetate
(5.0 mg, 0.01 mmol, 0.10 equiv), benzoquinone (21.6 mg, 0.2 mmol,
2.0 equiv), benzyl tosylcarbamate (58.2 mg, 0.2 mmol, 2.0 equiv),
DIPEA (0.77 mg, 0.006 mmol, 0.06 equiv), and a stir bar were then
sequentially added. The vial was fitted with a Teflon cap, and heated
to 45 ꢁC (with magnetic stirring) in an oil bath for 72 h. The vial was
removed, allowed to cool to room temperature, and thoroughly
rinsed into a 125 mL separatory funnel with ether (ca. 30 mL). The
organic phase was washed with 5% aq K2CO3 (6ꢂ10 mL), and the
aqueous rinses back-extracted with ether (2ꢂ30 mL). The com-
bined organic extracts were dried over MgSO4 and evaporated to
dryness. The crude product was purified by flash chromatography
on silica gel (10e40% EtOAc/hexanes) and evaporated to dryness.
Run 1 (47 mg, 0.065 mmol, 65%, starting material (2 mg, 5%) was
recovered); run 2 (53 mg, 0.072 mmol, 72%, no remaining starting
material). Average yield: 69%. White solid, 1H NMR (500 MHz,
CDC13) 7.69 (2H, d, J¼8.0 Hz, TseH), 7.33e7.31 (3H, m, PheH),
7.19e7.17 (4H, m, TseH and PheH), 5.72e5.66 (2H, m, CH]CH),
5.35e5.26 (3H, m, OAcCH, BocNHCH, and BocNHCH), 5.08 (2H, s,
OCH2Ph), 4.45e4.38 (2H, m, CbzTsNCH2), 3.88e3.87 (1H, m,
TBSNCH), 2.44e2.40 (1H, m, CH]CHCH2CHOAc), 2.40 (3H, s,
PhCH3), 2.31e2.25 (1H, m, CH]CHCH2CHOAc), 2.06 (3H, s,
OCOCH3), 1.47 (9H, s, Boc), 0.90 (9H, s, TBS), 0.23 (3H, s, TBS), 0.18
(3H, s, TBS); 13C NMR (125 MHz, CDCl3) 173.8, 169.9, 154.7, 152.1,
144.6, 136.6, 134.6, 129.4, 128.9, 128.7, 128.6, 128.5, 128.4, 80.7, 71.9,
69.1, 59.1, 57.5, 48.4, 33.9, 28.4, 26.3, 21.7, 21.1, 19.1, ꢀ5.4, ꢀ5.9, one
carbon was overlapped in aryl carbon area; IR (film, cmꢀ1):
3400e3100 (br), 3033, 2956, 2931, 2900, 2860, 1738, 1529, 1506,
1456, 1365, 1307, 1290, 1253, 1234, 1171, 1090, 1059, 1028, 841, 825,
4.5. General procedure for Figure 3
4.5.1. (E)-4-(N-((Benzyloxy)carbonyl)-4-methylphenylsulfonamido)-
1-((2R,3R)-3-((tert-butoxycarbonyl)amino)-1-(tert-butyldime-
thylsilyl)-4-oxoazetidin-2-yl)but-2-en-1-yl acetate 12.
A one dram vial was charged with homoallylic acetate 11
(41.2 mg, 0.1 mmol, 1.0 equiv), followed by t-butyl methyl ether
(0.15 mL). 1,2-Bis(phenylsulfinyl)ethane palladium(II) acetate
(5.0 mg, 0.01 mmol, 0.10 equiv), benzoquinone (21.6 mg, 0.2 mmol,
2.0 equiv), benzyl tosylcarbamate (58.2 mg, 0.2 mmol, 2.0 equiv),
DIPEA (0.77 mg, 0.006 mmol, 0.06 equiv), and a stir bar were then
sequentially added. The vial was fitted with a Teflon cap, and heated
to 45 ꢁC (with magnetic stirring) in an oil bath for 72 h. The vial was
removed, allowed to cool to room temperature, and thoroughly
rinsed into a 125 mL separatory funnel with ether (ca. 30 mL). The
organic phase was washed with 5% aq K2CO3 (6ꢂ10 mL), and the
aqueous rinses back-extracted with ether (2ꢂ30 mL). The com-
bined organic extracts were dried over MgSO4 and evaporated to
dryness. The crude product was purified by flash chromatography
on silica gel (10e40% EtOAc/hexanes), and evaporated to dryness.
Run 1 (39 mg, 0.055 mmol, 55%), starting material (12 mg, 29%) was
recovered.); run 2 (39 mg, 0.055 mmol, 55%, Starting Material
(11 mg, 27% was recovered). Average yield: 55%, average recovered
starting material: 28%. (In both runs branched and Z-olefin isomers
were not observed. The diastereomeric ratio of products remained
814, 787, 768, 739, 700, 677, 596, 546; HRMS (ESI) m/z calcd for
25
C36H52N3O9SiS [MþH]þ: 730.3194, found 730.3208; [
a
]
þ5.2 (c
D
1.0, CHCl3).

X.(Ben) Qi et al. / Tetrahedron 66 (2010) 4816e4826
4825
4.6. General procedure for Figure 4
yellow solid. 1H NMR (500 MHz, CDC13) 5.69 (1H, ddd, J¼17.0, 10.0,
7.3 Hz, CH]CH2), 5.34e5.23 (4H, m, CH]CH2, BocNHCH, and
BocNHCH), 4.98 (1H, s, NH), 4.58 (1H, br d, J¼12.0 Hz,
TBSNCHCHOCONH), 4.03 (1H, ddd, , J¼11.5, 7.0, 5.0 Hz, NHCHCH]
CH2), 3.82e3.83 (1H, m, TBSNCH), 1.98e1.95 (1H, m, CH2CHCH]
CH2), 1.70 (1H, app. q, J¼12.0 Hz, CH2CHCH]CH2), 1.42 (9H, s, Boc),
0.98 (9H, s, TBS), 0.29 (3H, s, TBS), 0.25 (3H, s, TBS); 13C NMR
(125 MHz, CDCl3) 171.9, 155.1, 152.7, 136.7, 118.2, 80.7, 75.5, 59.8,
57.8, 53.8, 29.9, 28.4, 26.2, 18.8, ꢀ5.2, ꢀ5.5; IR (film, cmꢀ1):
3400e3100 (br), 2954, 2931, 2860, 1749, 1714, 1508, 1458, 1419,
1392, 1367, 1302, 1254, 1165, 1065, 1030, 1007, 841, 825, 812, 787,
735, 702; HRMS (ESI) m/z calcd for C20H35N3O5SiNa [MþNa]þ:
4.6.1. (ꢀ)-tert-Butyl-((3R,4R)-1-(tert-butyldimethylsilyl)-2-oxo-4-
((4S,5R)-2-oxo-4-vinyloxazolidin-5-yl)azetidin-3-yl)carbamate
(ꢀ)-15.
448.2244, found 448.2242; [
a]
20 ꢀ143.5 (c 0.1, CHCl3).
To a half dram vial was added tert-butyl ((2R,3R)-1-(tert- butyl-
dimethylsilyl)-2-((4S,5S)-3-((4-nitrophenyl)sulfonyl)-2-oxo-4-
vinyloxazolidin-5-yl-4-oxoazetidin-3-yl)carbamate (ꢀ)-8 (50.0 mg,
0.084 mmol, 1 equiv), K2CO3 (35 mg, 0.252 mmol, 3 equiv) and
a Teflon stir bar. The reaction flask was purged with argon followed
by the addition of DMF (0.22 mL). The mixture was cooled to 0 ꢁC
D
4.6.3. (E)-4-(((Benzyloxy)carbonyl)amino)-1-((2R,3R)-3-((tert-bu-
toxycarbonyl)amino)-1-(tert-butyldimethylsilyl)-4-oxoazetidin-2-yl)
but-2-en-1-yl acetate 17.
OAc
then PhSH was added (10.3 mL, 0.1 mmol,1.2 equiv) dropwise slowly.
BocHN
NHCBz
The reaction mixture was stirred at 0 ꢁC for 1 h then filtered over
a silica plug followed by 150 mL of 10% MeOH/methylene chloride.
The crude mixture was concentrated in vacuo to remove the
remaining DMF. Purification by flash column chromatography (3%
MeOH/methylene chloride) yielded 32 mg (93%) of a light yellow
solid). 1H NMR (500 MHz, CDC13) 5.83 (1H, ddd, J¼17.0, 10.0, 6.5 Hz,
CH]CH2), 5.32 (1H, d, J¼17.0 Hz, CH]CH2), 5.28 (1H, d, J¼10 Hz,
CH]CH2), 5.16 (1H, dd, J¼7.0, 5.5 Hz, BocNHCH), 5.11 (1H, d,
J¼7.0 Hz, BocNHCH), 5.05 (1H, s, NH), 4.22 (1H, dd, J¼9.0, 2.5 Hz,
OCHCHNH), 4.05e4.06 (1H, m, OCHCHNH), 3.91 (1H, dd, J¼9.0,
5.5 Hz, TBSNCH), 1.43 (9H, s, Boc), 0.99 (9H, s, TBS), 0.30 (3H, s, TBS),
0.29 (3H, s, TBS); 13C NMR (125 MHz, CDCl3)172.0,157.7,155.3,135.2,
117.9, 82.9, 81.4, 59.5, 58.4, 56.4, 28.4, 26.6, 18.7, ꢀ5.1, ꢀ5.2; IR (film,
cmꢀ1):3400e3100 (br), 2958, 2927, 2856, 2927, 2856, 1749, 1716,
1531,1464,1392,1367,1255,1163,1063,1016, 993, 941, 842, 825, 814,
787, 736; HRMS (ESI) m/z calcd for C19H34N3O5Si [MþH]þ: 412.2268,
NTBS
17
O
A flame-dried 10 mL pear-shape flask was charged with a stir bar,
above allylic amine 12 (89.0 mg, 0.125 mmol, 1 equiv) and DME
(1.5 mL). The reaction mixture was cooled to ꢀ78 ꢁC and a portion of
the sodium/naphthalene mixture was added to the substrate drop-
wise over w5 min (1.2 mL sodium/naphthalene mixture, w1 mmol,
w8 equiv, the color was changed from dark green to light green, then
light yellow, then dark green). Note that 1.0e1.1 mL of sodium/naph-
thalene mixture turns the reaction dark green, then a small amount
more was added. The reaction mixture was stirred at ꢀ78 ꢁC for
30 min then quenched with NH4Cl (2 mL). The cooling bath was re-
moved and the reaction mixture was allowed to warm to room tem-
perature. The mixture was transferred to a separatory funnel using
ether (15 mL) and brine (5 mL) to aid the transfer. The aqueous and
organic layers were separated and the aqueous layer was extracted
using ether (7ꢂ15 mL). The combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo. The crude reaction mix-
ture was purified by flash chromatography on silica gel (10% to 40%
EtOAc/hexanes) and evaporated to dryness. (65 mg product, white
solid, 84% yield); 1H NMR (500 MHz, CDC13) of mixture: 7.36e7.30
(10H, m, 2ꢂPheH), 5.81e5.76 (2H, m), 5.74e5.68 (2H, m), 5.59e5.55
(1H, m), 5.37e5.35 (1H, m), 5.30e5.25 (3H, m), 5.12e5.07(5H, m), 5.01
(1H, br s), 4.83 (1H, br s), 3.91e3.84 (4H, m), 3.79e3.66 (2H, m), 2.12
(3H, s, OCOCH3), 2.10 (3H, s, OCOCH3),1.43 (9H, s, Boc),1.41 (9H, s, Boc),
0.95 (9H, s, TBS), 0.93 (9H, s, TBS), 0.27 (3H, s, TBS), 0.26 (3H, s, TBS),
0.24 (3H, s, TBS), 0.20 (3H, s, TBS); 13C NMR (125 MHz, CDCl3) one
diastereomer: 173.6, 169.6, 156.3, 154.8, 136.4, 132.6, 128.6, 128.3,
125.8, 80.6, 72.4, 67.0, 59.3, 58.7, 42.5, 28.4, 26.3, 21.2,19.0, ꢀ5.2, ꢀ5.4;
another diastereomer: 172.8, 169.9, 156.5, 155.0, 136.6, 130.8, 128.6,
128.2,126.5, 80.5, 73.1, 67.0, 59.8, 58.4, 42.6, 28.4, 26.4, 21.5,18.7, ꢀ5.4,
ꢀ5.8;(onecarbonwasoverlapped inarylcarbonarea);IR (film, cmꢀ1):
3500e3100 (br), 2956, 2931, 2902, 2858,1738, 1716, 1525, 1470,1456,
1367,1252,1232,1164,1059,1024, 970, 841, 825, 812, 785; HRMS (ESI)
m/z calcd for C28H44N3O7Si [MþH]þ: 562.2949, found 562.2951.
To prepare the sodium-naphthalene reagent, a flame-dried
50 mL round bottom flask was charged with a stir bar, naphthalene
(790 mg, 6.16 mmol, 1.2 equiv), DME (6 mL), and small pieces of
sodium metal (118 mg, 5.13 mmol, 1 equiv, washed by hexane and
then MeOH quickly). This mixture was allowed to vigorously stir
overnight for approximately 12 h. The next morning the mixture
was a dark green. (Note that mixtures of sodium/naphthalene that are
brown typically give poor results and should be discarded).
found 412.2281;[
a]
20 ꢀ32.5 (c 0.4, CHCl3).
D
The stereochemistry of the syn- and anti-diastereomers of
oxazolidinone was determined through their vicinal coupling
constants (3JHyHz). In general, anti-oxazolidinones show a coupling
constant within 0e4.8 Hz, and the syn-oxazolidinones show
a coupling constant within 6.2e8.4 Hz. For this specific example,
3
the JHyHz of anti-isomers 3 is 2.5 Hz. Ref. 4b provides a more de-
tailed description of relative data.
4.6.2. (ꢀ)-tert-Butyl-((3R,4R)-1-(tert-butyldimethylsilyl)-2-oxo-4-
((4R,6S)-2-oxo-4-vinyl-1,3-oxazinan-6-yl)azetidin-3-yl)carbamate
(ꢀ)-16.
O
O
NH
BocHN
O
NTBS
(-)-16
To a a half dram vial was added tert-butyl ((2R,3R)-1-(tert-
butyldimethylsilyl)-2-((4S,6R)-3-((4-nitrophenyl)sulfonyl)-2-oxo-
4-vinyl-1,3-oxazinan-6-yl)-4-oxoazetidin-3-yl)carbamate (þ)-10
(35 mg, 0.057 mmol, 1 equiv), K2CO3 (24 mg, 0.172 mmol, 3 equiv),
and a Teflon stir bar. The reaction flask was purged with argon
followed by the addition of DMF (0.15 mL). The mixture was cooled
to 0 ꢁC then PhSH was added (7
mL, 0.07 mmol, 1.2 equiv) dropwise
slowly. The reaction mixture was stirred at 0 ꢁC for 1 h then filtered
over a silica plug followed by 150 mL of 10% MeOH/methylene
chloride. The crude mixture was concentrated in vacuo to remove
the remaining DMF. Purification by flash column chromatography
(3% MeOH/methylene chloride) yielded 22 mg (yield: 90%) of a light

4826
X.(Ben) Qi et al. / Tetrahedron 66 (2010) 4816e4826
4.6.4. (þ)-(S)-5-(((Benzyloxy)carbonyl)amino)-1-((2R,3R)-3-((tert-
butoxycarbonyl)amino)-1-(tert-butyldimethylsilyl)-4-oxoazetidin-2-
yl)pent-3-en-1-yl acetate (þ)-18.
References and notes
1. Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46 and references
therein.
2. General CeH oxidation, aminations, alkylations: (a) Muller, P.; Fruit, C. Chem.
Rev. 2003, 103, 2905; (b) Espino, C. G.; DuBois, J. Modern Rhodium-Catalyzed
Organic Reactions Wiley-VCH Verlag GmbH & KGaA: Weinheim,; 2005; 379; (c)
Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439 and references therein; (d)
Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174; (e) Chen, M. S.;
White, M. C. Science 2007, 318, 783; (f) Davies, H. M. L.; Manning, J. R. Nature
2008, 451, 417; (g) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008,
41, 1013; (h) Lafrance, M.; Lapointe, D.; Fagnou, K. Tetrahedron 2008, 64, 6015;
(i) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48,
5094; (j) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593; (k) Chen, M. S.;
White, M. C. Science 2010, 327, 566; (l) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-
Kreutzer, J.; Baudoin, O. Chem.dEur. J. 2010, 16, 2654.
3. Pd-catalyzed allylic CeH oxidations: (a) Chen, M. S.; White, M. C. J. Am. Chem. Soc.
2004, 126, 1346; (b) Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C. J. Am.
Chem. Soc. 2005, 127, 6970; (c) Fraunhoffer, K. F.; Prabagaran, N.; Sirois, L. E.; White,
M. C. J. Am. Chem. Soc. 2006, 128, 9032; (d) Delcamp, J. H.; White, M. C. J. Am. Chem.
Soc. 2006, 128, 15076; (e) Covell, D. J.; White, M. C. Angew. Chem., Int. Ed. 2008, 47,
A flame-dried 10 mL pear-shape flask was charged with a stir bar,
allylic amine (þ)-14 (135 mg, 0.185 mmol,1 equiv), and DME (2.5 mL).
The reaction mixture was cooled to ꢀ78 ꢁC and a portion of the so-
dium-naphthalene mixture was added to the substrate dropwise over
w5 min (1.5 mL sodium/naphthalene mixture, w1.48 mmol,
w8 equiv, the color was changed from dark green to light green, then
light yellow, then dark green). Note that 1.4e1.5 mL of sodium/naph-
thalene mixture turns the reaction dark green, then a small amount
morewas added. The reaction mixturewasstirredat ꢀ78 ꢁCfor30 min
then quenched with NH4Cl (2 mL). The cooling bath was removed and
the reaction mixture was allowed to warm to room temperature. The
mixturewas transferred to a separatory funnel using ether (15 mL) and
brine (5 mL) to aid the transfer. The aqueous and organic layers were
separated and the aqueous layer was extracted using ether (3ꢂ15 mL).
The combined organic layers were dried over MgSO4, filtered, and
concentrated in vacuo. The crude reaction mixture was purified by
flash chromatography on silica gel (10e40% EtOAc/hexanes), and
evaporated to dryness(95 mg product, 89%yield). White solid,1HNMR
(500 MHz, CDC13) 7.39e7.32 (5H, m, PheH), 5.62e5.51 (2H, m, CH]
CH), 5.33e5.26 (3H, m, OAcCH, BocNHCH, and BocNHCH), 5.13 (2H, s,
OCH2Ph), 4.84 (1H, br s, CbzNH), 3.86e3.85 (1H, m, TBSNCH),
3.80e3.78 (2H, m, CbzTsNCH2), 2.46e2.37 (1H, m, CH]CHCH2CHOAc),
2.31e2.25(1H, m, CH]CHCH2CHOAc),2.11(3H,s,OCOCH3),1.48(9H, s,
Boc), 0.94 (9H, s, TBS), 0.26 (3H, s, TBS), 0.20 (3H, s, TBS); 13C NMR
(125 MHz, CDCl3) 173.7, 170.0, 156.3, 154.8, 136.6, 130.6, 128.7, 128.3,
128.3, 126.6, 80.8, 72.2, 66.9, 59.2, 57.6, 42.7, 34.0, 28.4, 26.3, 21.2, 19.1,
ꢀ5.3, ꢀ5.8; IR (film, cmꢀ1):3400e3100 (br), 2954, 2931, 2899, 2860,
1738,1714,1527,1471,1456,1367,1250,1236,1167,1061,1026, 841, 825,
787, 737; HRMS (ESI) m/z calcd for C29H46N3O7Si [MþH]þ: 576.3105,
6448 For
a linear allylic acetoxylation system using DMA solvent see:
(f) Mitsudome, T.; Umetani, T.; Nosaka, N.; Mori, K.; Mizugaki, T.; Ebitani, K.;
Kaneda, K. Angew. Chem., Int. Ed. 2006, 45, 481; (g) Pilarski, L. T.; Selander, N.; Bose,
D.; Szabo, K. J. Org. Lett. 2009,11, 5518; (h) Lin, B.-L.; Labinger, J. A.; Bercaw, J. E. Can. J.
Chem. 2009, 87, 264; (i) Thiery, C.; Aouf, J.; Belloy, D.; Harakat, J.; Le Bras, J.; Muzart.
J. Org. Chem. 2010, 75,1771; (j) Henderson, W. H.; Check, C. T.; Proust, N.; Stambuli, J.
P. Org. Lett. 2010, 12, 824.
4. Pd-catalyzed allylic CeH aminations: (a) For seminal work on formal allylic
CeH amination that may be proceeding via an aminopalladation pathways see:
Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996,
61, 3584; (b) Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc. 2007, 129, 7274; (c)
Reed, S. A.; White, M. C. J. Am. Chem. Soc. 2008, 130, 3316 For a similar system
using DMA solvent see: (d) Liu, G.; Yin, G.; Wu, L. Angew. Chem., Int. Ed. 2008, 47,
4733; (e) Rice, G. T.; White, M. C. J. Am. Chem. Soc. 2009, 131, 11707; (f)Reed, S. A.;
Mazzotti, A. R.; White, M. C. J. Am. Chem. Soc. 2009, 131,11701 For a system that also
uses Pd(II)/bis-sulfoxide catalysis see: (g) Nahra, F.; Liron, F.; Prestat, G.; Mealli, C.;
Messaoudi, A.; Poli, G. Chem.dEur. J. 2009, 15, 11078 For a system that also uses Cr
(salen)catalysis see: (h) Wu, L.; Qiu, S.; Liu, G. Org.Lett. 2009,11, 2707; (i) Shimizu, Y.;
Obora, Y.; Ishii, Y. Org. Lett. 2010, 12, 1372.
5. Pd-catalyzed allylic CdH alkylations: (a) Young, A. J.; White, M. C. J. Am. Chem.
Soc. 2008, 130, 14090 For a system that also uses Pd(II)/bis-sulfoxide catalysis
see: (b) Lin, S.; Song, C.-X.; Cai, G.-X.; Wang, W.-H.; Shi, Z.-J. J. Am. Chem. Soc.
2008, 130, 12901.
6. Streamlining synthesis via late-stage CeH oxidation: (a) Fraunhoffer, K. J.;
Bachovchin, D. A.; White, M. C. Org. Lett. 2005, 7, 223; (b) Covell, D. J.;
Vermeulen, N. A.; White, M. C. Angew. Chem., Int. Ed. 2006, 45, 8217; (c) Stang,
E. M.; White, M. C. Nat. Chem. 2009, 1, 547 For excellent reviews: (d) Hoffman,
R. W. Synthesis 2006, 21, 3531; (e) Hoffman, R. W. Elements of Synthesis Planning;
Springer: Heidelberg, 2009; For some elegant examples of late stage CeH hy-
droxylation and amination see: (f) Wender, P. A.; Hilinski, M. K.; Mayweg, A. V.
W. Org. Lett. 2005, 7, 79; (g) Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125,
11510; (h) Ref. 2e,2k.
found 576.3118;[
a
]
20 þ1.1 (c 1.0, CHCl3).
D
7. Deshmukh, A. R. A. S.; Bhawal, B. M.;Krishnaswamy, D.; Govande, V. V.; Shinkre, B. A.;
Jayanthi, A. Current Med. Chem. 2004, 11, 1889.
8. Ojima, I. Acc. Chem. Res. 1995, 28, 383.
Acknowledgements
9. (a) Georg, G. I. The Organic Chemistry of b-Lactams; VCH: New York, NY, 1993.
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M.C.W. and X.Q. are grateful to Pfizer for a grant to study direct
modifications of complex natural product-based compounds and
preparation of novel analogues or metabolites. M.C.W. and G.T.R.
are grateful to NIH/NIGMS (grant no. GM076153, and ARRA sup-
plemental funding) for support in the discovery and development
of Pd/bis-sulfoxide-catalyzed allylic CeH aminations including the
Lewis acid accelerating effect disclosed here.
11. Rogers, M. M.; Kotov, V.; Chatwichien, J.; Stahl, S. S. Org. Lett. 2007, 9, 4331 and
references therein.
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Chem. Soc. 1996, 118, 10924; (b) Jacobsen, E. N.; Kakiuchi, F.; Konsler, R. G.;
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Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.04.064.