An Asymmetric Vinylogous Michael Cascade of Silyl Glyoximide, Vinyl Grignard, and Nitroalkenes via Long Range Stereoinduction

Article abstract of DOI:10.1021/acs.joc.5b02693

A diastereoselective auxiliary-mediated vinylation/[1,2]-Brook rearrangement/vinylogous Michael cascade of silyl glyoximide, vinylmagnesium bromide, and nitroalkenes is described. The reaction occurs with complete regio- and diastereocontrol in good yield. The diastereoselectivity is induced by a rare instance of 1,7-chirality transfer that is hypothesized to arise from a trans-multihetero-decalin transition state. (Chemical Equation).

Full text of DOI:10.1021/acs.joc.5b02693

Note
pubs.acs.org/joc
An Asymmetric Vinylogous Michael Cascade of Silyl Glyoximide,
Vinyl Grignard, and Nitroalkenes via Long Range Stereoinduction
Gregory R. Boyce† and Jeffrey S. Johnson*,‡
†Department of Chemistry and Physics, Florida Gulf Coast University, Fort Myers, Florida 33965, United States
‡Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599-3290, United States
S
* Supporting Information
ABSTRACT: A diastereoselective auxiliary-mediated vinyl-
ation/[1,2]-Brook rearrangement/vinylogous Michael cascade
of silyl glyoximide, vinylmagnesium bromide, and nitroalkenes
is described. The reaction occurs with complete regio- and
diastereocontrol in good yield. The diastereoselectivity is
induced by a rare instance of 1,7-chirality transfer that is
hypothesized to arise from a trans-multihetero-decalin
transition state.
described above all rely on deprotonation of a latent dienolate
precursor (Figure 1).
inylogous reactivity provides a distinct and atom
Veconomical approach for the direct γ-functionalization of
carbonyls to synthesize complex targets. Prototypical cases
involve the conversion of α,β-unsaturated carbonyls to their
derived dienolates, or synthetic equivalents thereof, and
electrophilic trapping at the γ-carbon. Although the vinylogous
Mukaiyama aldol1 and Mannich2 reactions have become well-
established, the vinylogous Michael reaction has received less
attention.3 A key selectivity issue is the site of trapping in the
extended π-system. Computational studies of frontier orbital
densities and HOMO coefficients of simple lithium metal-
lodienolates have established that α-trapping is favored over the
γ-position.1a,4 The majority of examples of the vinylogous
Michael reaction rely on substrates with an inherent preference
for γ-selectivity relative to α-trapping: butenolides or α,α-
dicyanoalkenes are commonly used.2
Despite these challenges, some impressive examples of γ-
functionalization via the vinylogous Michael reaction have been
reported with various latent nucleophiles in the past five years.
In 2010, Melchiorre and co-workers demonstrated that 3-
alkylcyclohex-2-en-1-ones could be employed as competent
nucleophiles in highly regio- and enantioselective organo-
catalytic vinylogous Michael reactions with β-nitrostyrenes.5
Jørgenson then demonstrated the use of enals as acyclic latent
dienolates in reactions with α-keto esters to construct
dihydropyrans via formal [4 + 2] cycloaddition.6 Linear
vinylogous Michael products were developed independently
by Schnieder7 and Xu8 that expanded the vinylogous
Mukaiyama Michael reaction (VMMR) to include aromatic
α,β-unsaturated ketones with enals to provide valuable 1,7-
dioxo compounds. In 2013, Wang and co-workers described
(salen)Mg-catalyzed vinylogous Michael additions between β-
alkyl chalcones and β-nitrostyrenes to give nitrocyclohexanols
in a formal [4 + 2] cycloaddition.9 In general, the integration of
functionality at the α-position is challenging, and the cases
Figure 1. Dienolate synthon: selected synthetic equivalents.
In 2010, we reported an alternative approach to the
vinylogous Michael reaction by achieving the requisite
dienolate via a vinylation/[1,2]-Brook rearrangement11 of silyl
glyoxylates. The latter are a reliable class of conjunctive
reagents for the union of nucleophilic and electrophilic
partners.10 The title reaction was envisioned based on the
Received: November 24, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02693
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The Journal of Organic Chemistry
Note
seminal publications by the Kuwajima and Reich groups on
silyloxyallyl- and silyloxypropargyl anionic systems.12 Addition
of vinyl Grignard11 or acetylide13 nucleophiles to silyl
glyoxylates create (Z)-glycolate enolates14 that can either
engage a secondary electrophile with either α- or γ-trapping.
The identity of the secondary electrophile employed in silyl
glyoxylate couplings functions as a regiochemical switch:
carbonyl electrophiles provide predominantly α-adducts,15
whereas nitroalkenes and cyanoolefins provide exclusively γ-
addition via trapping of an unusual α-keto ester homoenolate
synthetic equivalent. Although the vinylogous Michael method-
ology provided good yields and complete regioselectivity
favoring the γ-adduct, the utility was limited by the lack of
stereoselectivity in forming the new chiral center.
silanes developed by Hsung and co-workers, held promise as
asymmetric conjunctive reagents.19
Herein, we describe vinylation-initiated vinylogous Michael
cascades of silyl glyoximides, nitroalkenes, and vinylmagnesium
bromide. This work builds upon the initial finding reported in
the original three-component coupling of silyl glyoxylates, vinyl
Grignard, and nitroalkenes.11 The disclosed methodology
affords (Z)-enolsilanes with complete regio- and diastereose-
lectivity by exploiting a rare example of long-range 1,7-chirality
transfer to provide complete asymmetric induction. Compared
to other vinylogous Michael methodologies, silyl glyoximides
offer a conceptually distinct approach to the requisite dienolate
nucleophile via a [1,2]-Brook rearrangement20 that provides α-
heteroatom functionality currently inaccessible through other
methods (Scheme 1). The three-component coupling yields
densely functionalized compounds, providing an enolsilane,
nitro group, and acyl oxazolidinone21 in the product.
Inducing asymmetry in the three-component couplings of
silyl glyoxylates has been a topic of significant interest with
instructive examples highlighted in Figure 2. Useful levels of
Scheme 1. Vinylmagnesium Bromide-Initiated Vinylogous
Coupling of Silyl Glyoximide with Nitroalkenes
Because the synthesis of the desired silyl glyoximide 1 has
been reported to provide a low yield,19 we sought to optimize
the sequence (Scheme 2). We employed the aerobic oxidative
carbamoylation protocol of Stahl and co-workers,22 which
utilized a 5-fold excess of the oxazolidinone to provide a
significant increase in yield from 23 to 74%. The excess of the
oxazolidinone is required to inhibit homocoupling of the TES-
alkyne; however, because the excess is not consumed in the
reaction, the oxazolidinone can be recovered by flash
chromatography. For the subsequent oxidation of the ynamide
to the imido acyl silane, the reported 5 mol % catalyst loading
was examined to minimize the use of the ruthenium complex.
For this substrate, the catalyst loading could be decreased from
5 to 1 mol % of ruthenium(IV) oxide hydrate without adversely
affecting the yield (81%). This two-step synthesis provides a
60% overall yield of the imido acyl silane, which compares
favorably to the synthesis of the original silyl glyoxylate
reagent.23
With a reliable synthesis of the primary electrophile in hand,
the feasibility of the title process was investigated. An initial
reaction of the imido acyl silane, β-nitrostyrene, and vinyl
Grignard at −78 °C followed by warming to room temperature
provided the desired three-component coupling product 3a in
47% yield as a single diastereomer. The absolute configuration
was determined by conversion to the known γ-nitroaldehyde by
ozonolysis.24 Analysis of the byproducts demonstrated that
vinylmagnesium bromide acts as a highly discriminating
nucleophile in this reaction manifold with a strong preference
for the acyl silane over the nitroalkene secondary electrophile:
only trace quantities of direct Grignard addition to the
nitroalkene were observed. Optimization revealed that a 50%
Figure 2. Diastereoselective silyl glyoxylate couplings.
diastereoselectivity (dr 15:1) were initially realized in the
tandem Oppenauer oxidation/aldol reaction using an 8-
phenylmenthol auxiliary. Although this result demonstrates
that a chiral auxiliary at the ester moiety can provide high levels
of selectivity, the selectivity was highly substrate dependent and
could not be developed to include a wider scope.16 Schmitt et
al. found similar substrate dependence in the glycolate Michael
reaction: 5:1 diastereoselection was imparted by the chiral
auxiliary. In independent reports, Greszler et al.17 and Yao and
Lu18 demonstrated that chiral electrophiles can successfully
provide high levels of stereoinduction via a proposed chairlike
transition state. After several of our attempts to accomplish the
vinylogous Michael cascade asymmetrically with silyl glyoxylate
and chiral catalysts failed, a suitable chiral auxiliary was sought
to confer asymmetry. Silyl glyoximides, a new class of acyl
B
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Note
Scheme 2. Optimized Synthesis of Silyl Glyoximide 1
excess of the nitroalkene improves the yield of the coupling to
75%. Unlike the related silyl glyoxylate coupling that required
excess silyl glyoxylate to compensate for oligomerization,11 the
imido acyl silane coupling produces no observable oligomeriza-
tion. This absence of oligomerization may be due to several
factors, including the added steric bulk of the chiral auxiliary
and the altered electronics of the dienolate. The (Z)-geometry
of the enolsilane was determined by analogy to the related
enolsilanes from the silyl glyoxylate vinylogous Michael
cascade.11 This (Z)-selectivity is also consistent with the
homoenolate precedent set by the research groups of Reich and
Kuwajima.12,14
attempted, but productive three-component coupling was not
observed.
With high levels of stereoinduction for the vinylation
coupling, we sought to utilize the silyl glyoximide to impart
facial selectivity into the three-component alkynyl coupling
previously reported by our group.13 Substituting the vinyl
Grignard with an alkynyl Grignard was demonstrated to
produce stereodefined silyloxyallenes 4 in a highly diaster-
eoselective manner as illustrated in Scheme 3. Density
Scheme 3. Comparison of Diastereoselectivity between Silyl
Glyoxylates and Silyl Glyoximides
With suitable conditions in hand, an examination of the
allowable steric and electronic parameters of the coupling in the
nitroalkene component was undertaken. A variety of alkyl,
alkenyl, aryl, and heteroaryl nitroalkenes were submitted to the
reaction conditions, and the results are compiled in Table 1.
Table 1. Synthesis of (Z)-Enolsilanes via Three-Component
Coupling
a
b
c
entry
product
R
yield (%)
dr
functional theory (DFT) calculations supported a highly
organized closed transition state where chelation between the
nitro group and the metallodienolate enabled a fixed approach
of the electrophile with respect to the (Z)-glycolate enolate.
Exposing the silyl glyoximide to the reported coupling
conditions provided 5 as a 1:1 mix of two (of four possible)
diastereomers (as judged by 1H NMR spectroscopic analysis of
the unpurified reaction mixture).
1
3a
3b
3c
3d
3e
3f
Ph
75
56
61
40
60
57
54
70
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
2
o-MeC6H5
p- MeC6H5
o-ClC6H5
p-ClC6H5
piperonyl
2-thienyl
2-furyl
3
4
5
6
7
3g
3h
3i
Because 1,7-chiral induction is rare,25 we sought to
understand the transition state that imparts such a high level
of diastereoselectivity. A chelation-controlled model for this
coupling would rely on nitroalkene activation by the Lewis
8
d
9
(E)-CHCHPh
69
10
11
12
3j
Et
56
63
62
3k
3l
iPr
+
CH2iPr
acidic MgBr portion of the (Z)-metallodienolate to guide the
a
b
approach of the former. We invoked a strong coordination
effect of the nitro group to the magnesium counterion in a
related silyl glyoxylate coupling with acetylides that was
corroborated by DFT-calculations. This coordination was
further empirically supported by the inability of a poor chelator,
benzylidenemalononitrile, to perform with the same level of
selectivity in the reaction.13 The electron-rich oxazolidinone
can form a six-membered chelate to the magnesium counterion
to provide rigidity and enforce facial selectivity from the
oxazolidinone stereocenter. The nitroalkene approach can then
be directed by coordination to the Lewis acid, creating a trans-
decalin transition state 6 as shown in Figure 3.
All reactions were conducted with [1]0 = 0.1 M. Isolated yield.
Diastereomeric ratio estimated from integration of H NMR spectra
of unpurified mixtures. Approximately 85% purity.
c
1
d
The yields of three-component coupling products ranged from
40 to 75% with the ortho-substituted β-nitrostyrene substrates
providing the lowest yields. Alkyl-, alkenyl-, and heteroar-
omatic-substituted nitroalkenes, as well as the piperonal-derived
3f and cinnamaldehyde-derived 3i, were well-tolerated. Nitro-
diene 3i exhibited 1,4-selectivity in the face of potentially
competing 1,6-addition, a circumstance that may provide a hint
to the operative transition state of the three-component
coupling (vide infra). All examples provided greater than 20:1
diastereoselectivity as judged by 1H NMR spectroscopic
analysis of the unpurified reaction mixture. α-Substituted
Grignard reagents (e.g., 2-propenylmagnesium bromide) were
Significant precedent exists for such decalin transition states
when multiple electronic interactions are possible.26 The
multiheterobicyclo[4.4.0]decane framework of the transition
state relies on the electrostatic interaction between the nitrogen
C
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plug (100% dichloromethane) to afford 370.0 mg (86%) of product 1
as a yellow solid. The title compound’s properties matched the
reported characterization data.15
General Procedure for Synthesis of Nitroalkenes (2a−2l).28a To
the appropriate aldehyde (14.2 mmol) were added 2 mL of
nitromethane and 25 mL of MeOH. This solution was cooled to 0
°C, and 35 mL of 1 M NaOH solution was added portionwise. The
solution was allowed to stir for 2 h and warm to room temperature.
The mixture was then slowly added to an aqueous 6 M HCl solution
cooled to 0 °C and stirred for 15 min. The mixture was washed with
dichloromethane (3 × 15 mL). The organic layers were combined,
washed with brine, dried over Na2SO4, and concentrated in vacuo. The
crude mixture was purified by flash chromatography (10% EtOAc/
hexanes) to afford the desired nitroalkene in yields ranging from 40 to
80% depending on the substrate. 1H NMR spectral data matched
those reported in the literature.28
General Procedure for the Synthesis of Enolsilanes (3a−3l). The
silyl glyoximide and nitroalkene were added to an oven-dried vial. The
vial was then purged with N2, and toluene (0.1 M) was added. The
resulting solution was cooled to −78 °C using an acetone/dry ice bath,
and vinylmagnesium bromide was added dropwise to the solution.
Once the addition was complete, the reaction was allowed to warm to
room temperature and stirred for 1 h; it was then diluted with diethyl
ether (5 mL) and quenched with saturated ammonium chloride (5
mL). The resulting mixture was stirred for 10 min. The layers were
separated, and the aqueous layer was extracted with ethyl acetate (3 ×
10 mL). The organic extracts were combined, washed with brine (5
mL), dried with magnesium sulfate, and concentrated in vacuo. The
crude mixture was purified by flash chromatography (25% EtOAc/
hexanes) to afford products 3a−l.
(R)-3-((S,Z)-6-Nitro-5-phenyl-2-((triethylsilyl)oxy)hex-2-enoyl)-4-
phenyloxazolidin-2-one (3a). The title compound was prepared
according to the general procedure using imide 1 (50.0 mg, 0.150
mmol, 1.0 equiv), nitroalkene 2a28a (33.6 mg, 0.225 mmol, 1.5 equiv),
and vinylmagnesium bromide (0.23 mL, 0.230 mmol, 1.5 equiv),
affording 57.4 mg (75%) of the product as a yellow oil. Analytical data
for 3a: IR (thin film, cm−1) 3436, 3064, 3032, 2957, 2913, 2877, 1785,
1692, 1644, 1552, 1381, 1320, 1204, 1157; 1H NMR (400 MHz,
CDCl3) δ 7.41−7.24 (m, 10H), 5.51−5.47 (m, 2H), 4.75−4.63 (m,
3H), 4.26 (dd, J = 8.4, 7.2 Hz, 1H), 3.70−3.62 (m, 1H), 2.71−2.55
(m, 2H), 0.97 (dd, J = 8, 7.6 Hz, 9H), 0.67 (q, J = 8 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 165.9, 153.0, 144.6, 139.3, 137.2, 129.1,
129.0, 128.9, 127.7, 127.3, 126.4, 117.9, 79.5, 69.8, 58.5, 43.5, 29.6, 6.5,
5.2 ; TLC (20% EtOAc/hexanes) Rf 0.36; HRMS (ESI+) calcd for
C27H34N2O6Si+Na, 533.2084; found, 533.2099.
(R)-3-((S,Z)-6-Nitro-5-(o-tolyl)-2-((triethylsilyl)oxy)hex-2-enoyl)-4-
phenyloxazolidin-2-one (3b). The title compound was prepared
according to the general procedure using imide 1 (50.0 mg, 0.150
mmol, 1.0 equiv), nitroalkene 2b28a (38.0 mg, 0.225 mmol, 1.5 equiv),
and vinylmagnesium bromide (0.23 mL, 0.230 mmol, 1.5 equiv),
affording 44.0 mg (56%) of the product as a yellow oil. Analytical data
for 3b: IR (thin film, cm−1) 2877, 2360, 1788, 1380, 1204, 746, 528;
1H NMR (600 MHz, CDCl3) 7.34−7.18 (m, 9H), 5.46−5.38 (m, 2H),
Figure 3. Proposed trans-decalin transition state.
and the electron-dense α-position of the (Z)-metallodienolate.
This orientation should also enable a stabilizing πCC
→
π*NO interaction. This transition state would place the
substituent of the nitroalkene into a desirable pseudoequatorial
position that leads to the observed stereoisomer.
The three-component coupling of silyl glyoximide, vinyl-
magnesium bromide, and nitroalkenes to provide (Z)-
enolsilanes with exceptional diastereoselectivity and good yields
for a diverse substrate scope is disclosed. The high level of
stereoinduction arising from a long-range 1,7-chiral transfer is
hypothesized to be a result of a highly organized trans-decalin
transition state. This reactivity pattern offers a unique
complement to known acyclic vinylogous Michael method-
ologies by providing access to α-substituted linear products
with a densely functionalized core. The (Z)-stereochemistry of
the enolsilane prevents the Henry cyclization observed by
Wang and co-workers, enabling the isolation of linear
vinylogous products for the first time.
EXPERIMENTAL SECTION
■
General Information. Proton and carbon nuclear magnetic
resonance spectra (1H and 13C NMR) were recorded at 600 and
150 MHz, respectively, with solvent resonance as the internal standard
(1H NMR: CDCl3 at 7.26 ppm; 13C NMR: CDCl3 at 77.0 ppm). H
1
NMR data are reported as follows: chemical shift, multiplicity (s =
singlet, d = doublet, dd = doublet of doublets, t = triplet, q = quartet,
m = multiplet), coupling constants (Hz), and integration. Mass spectra
were obtained using an FT-ICR mass analyzer with electrospray
ionization. TLC visualization was accomplished with UV light and/or
either aqueous potassium permanganate (KMnO4) or aqueous ceric
ammonium molybdate (CAM) solution followed by heating. All
reactions were carried out under an atmosphere of nitrogen in oven-
dried glassware with magnetic stirring. Yield refers to isolated yield of
analytically pure material. Yields are reported for a specific experiment
and as a result may differ slightly from those found in the tables, which
are averages of at least two experiments. Dichloromethane,
tetrahydrofuran, and toluene were dried by passage through a column
of neutral alumina under nitrogen prior to use.27
Triethylsilyl Silyl Glyoximide (1). Sodium carbonate (118.7 mg, 1.12
mmol, 2 equiv), CuCl2 (15.0 mg, 0.112 mmol, 0.2 equiv), and (R)-4-
phenyloxazolidin-2-one (455.0 mg, 2.79 mmol, 5 equiv) were added to
an oven-dried round-bottom flask. The reaction flask was purged with
O2 three times prior to the addition of toluene (3 mL, 0.2 M) and
pyridine (0.09 mL, 1.12 mmol, 2 equiv). A balloon of O2 was attached,
and the reaction flask was placed in a preheated 70 °C oil bath.
(Triethylsilyl)acetylene (0.10 mL, 0.56 mmol, 1 equiv) in toluene (3
mL, 0.2 M) was added dropwise over 6 h via syringe pump. The
reaction was allowed to stir for 16 h and then cooled to room
temperature and filtered through Celite. The crude mixture was
concentrated in vacuo and then purified by flash chromatography with
25% EtOAc/hexanes to afford the requisite ynamide in 78% yield. The
ynamide stains best with KMnO4 and ultraviolet light. The unreacted
oxazolidinone can be recovered and reused by flushing the column
with 100% EtOAc. The ynamide (390.0 mg, 1.29 mmol, 1 equiv) was
then treated with NaIO4 (830.0 mg, 3.88 mmol, 3 equiv) and RuO2
hydrate (1.7 mg, 0.013 mmol, 0.01 equiv) in a dichloromethane/
acetonitrile/water (14 mL, 2/2/3 v/v) solution. The reaction was
vigorously stirred for 3 h at room temperature, filtered through Celite,
and concentrated in vacuo. The crude mixture was purified via silica
4.70−4.61 (m, 3H), 4.23−4.21 (m, 1H), 3.95−3.90 (m, 1H), 2.67−
2.62 (m, 1H), 2.50−2.45 (m, 1H), 2.32 (s, 3H), 0.93−0.90 (m, 9H),
0.64−0.60 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 166.0, 153.1,
144.7, 137.4, 137.1, 136.3, 131.0, 129.2, 129.0, 127.4, 126.7, 126.4,
125.5, 118.1, 79.1, 69.8, 58.5, 38.4, 29.2, 19.5, 6.6, 5.1; TLC (30%
EtOAc/hexanes) Rf 0.51; HRMS (ESI+) calcd for C28H36N2O6Si+H,
525.2421; found, 525.2426.
(R)-3-((S,Z)-6-Nitro-5-(p-tolyl)-2-((triethylsilyl)oxy)hex-2-enoyl)-4-
phenyloxazolidin-2-one (3c). The title compound was prepared
according to the general procedure using imide 1 (50.0 mg, 0.150
mmol, 1.0 equiv), nitroalkene 2c28a (38.0 mg, 0.225 mmol, 1.5 equiv),
and vinylmagnesium bromide (0.23 mL, 0.230 mmol, 1.5 equiv),
affording 45.0 mg (57%) of the product as a yellow oil. Analytical data
for 3c: IR (thin film, cm−1) 3032, 2956, 2915, 2877, 1787, 1693, 1552,
1
1458, 1320, 1204, 746, 701; H NMR (600 MHz, CDCl3) 7.39−7.11
(m, 9H), 5.50−5.47 (m, 2H), 4.73−4.69 (m, 2H), 4.63−4.60 (m, 1H),
4.27−4.24 (m, 1H), 2.70−2.65 (m, 1H), 2.55−2.50 (m, 2H), 2.37 (s,
D
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Note
3H), 0.96−0.93 (m, 9H), 0.67−0.63 (m, 6H); 13C NMR (125 MHz,
CDCl3) δ 153.1, 144.6, 137.4, 137.1, 136.3, 129.7, 129.2, 129.1, 127.2,
126.5, 118.4, 79.7, 69.9, 58.5, 43.3, 29.7, 21.1, 6.6, 5.1; TLC (30%
EtOAc/hexanes) Rf 0.50; HRMS (ESI+) calcd for C28H36N2O6Si+Na,
547.2240; found, 547.2262.
mg, 0.150 mmol, 1.0 equiv), nitroalkene 2h28b(32.0 mg, 0.225 mmol,
1.5 equiv), and vinylmagnesium bromide (0.23 mL, 0.230 mmol, 1.5
equiv), affording 49.0 mg (65%) of the product isolated as an orange
oil. Analytical data for 3h: IR (thin film, cm−1) 2957, 2877, 2360, 2341,
1
1787, 1693, 1555, 1379, 1321, 1204, 746, 700; H NMR (600 MHz,
(R)-3-((S,Z)-5-(o-Chlorophenyl)-6-nitro-2-((triethylsilyl)oxy)hex-2-
enoyl)-4-phenyloxazolidin-2-one (3d). The title compound was
prepared according to the general procedure using imide 1 (50.0
mg, 0.150 mmol, 1.0 equiv), nitroalkene 2d28b (41.0 mg, 0.225 mmol,
1.5 equiv), and vinylmagnesium bromide (0.23 mL, 0.230 mmol, 1.5
equiv), affording 35.0 mg (40%) of the product as a yellow oil.
Analytical data for 3d: IR (thin film, cm−1) 2957, 2877, 1786, 1693,
CDCl3) δ 7.37−7.30 (m, 7H), 6.32 (d, J = 1.8 Hz, 1H), 6.31(d, J = 1.8
Hz, 1H), 6.15−6.14 (m, 1H), 5.50−5.45 (m, 3H), 4.72−4.71 (m, 1H),
4.26−4.23 (m, 1H), 2.62−2.61 (m, 2H), 0.92−0.89 (m, 9H), 0.63−
0.59 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 166.0, 153.2, 152.2,
144.9, 142.3, 137.0, 129.2, 129.1, 126.5, 117.7, 110.4, 107.1, 69.9, 58.5,
37.2, 27.1, 6.6, 5.1; TLC (30% EtOAc/hexanes) Rf 0.44; HRMS
(ESI+) calcd for C25H32N2O7Si+Na, 523.1876; found, 523.1893.
(R)-3-((S,2Z,6E)-5-(Nitromethyl)-7-phenyl-2-((triethylsilyl)oxy)-
hepta-2,6-dienoyl)-4-phenyloxazolidin-2-one (3i). The title com-
pound was prepared according to the general procedure using imide 1
(50.0 mg, 0.150 mmol, 1.0 equiv), nitroalkene 2i28b (39.4 mg, 0.225
mmol, 1.5 equiv), and vinylmagnesium bromide (0.23 mL, 0.230
mmol, 1.5 equiv), affording 55.5 mg (69%) of the product as a yellow
oil. Analytical data for 3i: IR (thin film, cm−1) 2955, 2359, 1791, 1623,
1
1551, 1381, 1320, 1204, 1064, 1003, 747, 699; H NMR (600 MHz,
CDCl3) 7.40−7.23 (m, 9H), 5.46−5.40 (m, 2H), 4.79−4.70 (m, 3H),
4.25−4.19 (m, 2H), 2.69−2.63 (m, 2H), 0.92−0.89 (m, 9H), 0.63−
0.59 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 166.1, 153.1, 144.9,
137.1, 136.4, 134.0, 130.3, 129.2, 129.1, 128.8, 128.0, 127.4, 126.4,
126.2, 117.4, 77.6, 69.9, 58.5, 39.7, 28.0, 6.6, 5.2; TLC (30% EtOAc/
hexanes) Rf 0.47; HRMS (ESI+) calcd for C27H33ClN2O6Si+Na,
567.1694; found, 567.1707.
1
1507, 1331, 1205, 742, 535; H NMR (600 MHz, CDCl3) 7.37−7.25
(m, 10H), 6.98 (d, J = 16.2 Hz, 1H), 6.09−6.08 (m, 1H), 5.60−5.57
(m, 1H), 5.48−5.42 (m, 1H), 4.71 (t,, J = 3.0 Hz, 1H), 4.53−4.52 (m,
1H), 4.52 (d,, J = 9.0 Hz, 1H), 4.26−4.24 (m, 1H), 2.45−2.34 (m,
1H), 2.46−2.42 (m, 1H), 0.90−0.89 (m, 9H), 0.63−0.59 (m, 6H); 13C
NMR (125 MHz, CDCl3) δ 166.1, 153.2, 144.7, 137.1, 136.3, 133.3,
129.2, 129.1, 128.6, 127.9, 127.1, 126.5, 118.1, 79.0, 69.9, 58.6, 41.7,
28.4, 6.7, 5.1; TLC (30% EtOAc/hexanes) Rf 0.47; HRMS (ESI+)
calcd for C29H36N2O6SiNa, 559.2240; found, 559.2255.
(R)-3-((S,Z)-5-(p-Chlorophenyl)-6-nitro-2-((triethylsilyl)oxy)hex-2-
enoyl)-4-phenyloxazolidin-2-one (3e). The title compound was
prepared according to the general procedure using imide 1 (50.0
mg, 0.150 mmol, 1.0 equiv), nitroalkene 2e28b (41.0 mg, 0.225 mmol,
1.5 equiv), and vinylmagnesium bromide (0.23 mL, 0.230 mmol, 1.5
equiv), affording 49.0 mg (60%) of the product isolated as a yellow oil.
Analytical data for 3e: IR (thin film, cm−1) 2957, 2360, 1791, 1698,
1
1557, 1038, 700, 536; H NMR (600 MHz, CDCl3) δ 7.37−7.26 (m,
7H), 7.14 (d, J = 9.0 Hz, 2H), 5.45 (dd, J = 8.4, 7.2, 1H), 5.38 (q, 7.2
Hz, 1H), 4.72−4.68 (m, 1H) 4.61−4.59 (m, 1H), 4.27−4.24 (m, 1H),
3.61−3.56 (m, 1H), 2.60−2.50 (m, 2H), 0.92−0.89 (m, 9H), 0.61−
0.59 (m, 6H); 13C NMR (150 MHz, CDCl3) δ 165.9, 153.1, 144.9,
137.8, 137.1, 133.6, 129.2, 129.2, 129.1, 128.7, 126.5, 117.2, 79.2, 69.9,
58.5, 42.9, 29.5, 6.6, 5.2; TLC (30% EtOAc/hexanes) Rf 0.50; HRMS
(ESI+) calcd for C27H33ClN2O6Si+Na, 567.1694; found, 567.1710.
(R)-3-((S,Z)-5-(Benzo[d][1,3]dioxol-5-yl)-6-nitro-2-((triethylsilyl)-
oxy)-hex-2-enoyl)-4-phenyloxazolidin-2-one (3f). The title com-
pound was prepared according to the general procedure using imide
1 (50.0 mg, 0.150 mmol, 1.0 equiv), nitroalkene 2f28c (44.0 mg, 0.225
mmol, 1.5 equiv), and vinylmagnesium bromide (0.23 mL, 0.230
mmol, 1.5 equiv), affording 46.0 mg (55%) of the product as a yellow
oil. Analytical data for 3f: IR (thin film, cm−1) 2956, 2877, 2360, 1785,
1694, 1248, 1204, 1040, 745, 701; 1H NMR (600 MHz, CDCl3) 7.39−
7.27 (m, 5H), 6.61 (d, J = 8.4 Hz, 1H), 6.68−6.64 (m, 2H), 5.95 (s,
2H), 5.47−5.42 (m, 2H), 4.70 (t, J = 3.0 Hz, 1H), 4.65−4.62 (m, 1H),
4.55−4.51 (m, 1H), 4.26−4.22 (m, 1H), 3.53−3.49 (m, 1H), 2.62−
2.59 (m, 1H), 2.46- 2.44 (m, 1H), 0.92−0.90 (m, 9H), 0.63−0.59 (m,
6H); 13C NMR (125 MHz, CDCl3) δ 166.0, 153.1, 148.1, 147.1,
144.7, 137.1, 133.0, 129.2, 129.1, 126.5, 120.7, 118.1, 107.5, 101.2,
79.8, 69.9, 58.5, 43.4, 29.7, 6.6, 5.1; TLC (30% EtOAc/hexanes) Rf
0.47; HRMS (ESI+) calcd for C28H34N2O8Si+Na, 577.1982; found,
577.1995.
(R)-3-((R,Z)-5-(Nitromethyl)-2-((triethylsilyl)oxy)hept-2-enoyl)-4-
phenyloxazolidin-2-one (3j). The title compound was prepared
according to the general procedure using imide 1 (50.0 mg, 0.150
mmol, 1.0 equiv), nitroalkene 2j28c (23.0 mg, 0.225 mmol, 1.5 equiv),
and vinylmagnesium bromide (0.23 mL, 0.230 mmol, 1.5 equiv),
affording 35.0 mg (51%) of the product isolated as a clear oil.
Analytical data for 3j: IR (thin film, cm−1) 2959, 2877, 1789, 1696,
1
1002, 744, 700, 533; H NMR (600 MHz, CDCl3) δ 7.40−7.33 (m,
5H), 5.60−5.57 (m, 1H), 5.50−5.47 (m, 1H), 4.72 (t, J = 9 Hz, 1H),
4.38−4.32 (m, 2H), 4.28−4.25 (m, 1H), 2.40−2.17 (m, 3H) 1.45 (q, J
= 7.2 Hz, 2H), 0.98−0.89 (m, 12H), 0.63−0.59 (m, 6H); 13C NMR
(150 MHz, CDCl3) δ 166.1, 153.3, 144.6, 137.1, 129.2 129.1, 126.4,,
119.3, 78.6, 69.8, 58.6, 39.1, 26.9, 24.4, 10.8, 6.6, 5.2; TLC (20%
EtOAc/hexanes) Rf 0.32; HRMS (ESI+) calcd for C23H34N2O6Si+Na,
485.2084; found, 485.2092.
(R)-3-((S,Z)-6-Methyl-5-(nitromethyl)-2-((triethylsilyl)oxy)hept-2-
enoyl)-4-phenyloxazolidin-2-one (3k). The title compound was
prepared according to the general procedure using imide 1 (50.0
mg, 0.150 mmol, 1.0 equiv), nitroalkene 2k28c (29.0 mg, 0.225 mmol,
1.5 equiv), and vinylmagnesium bromide (0.23 mL, 0.230 mmol, 1.5
equiv), affording 34.5 mg (71%) of the product as a pale yellow oil.
Analytical data for 3k: IR (thin film, cm−1) 2459, 2877, 2360, 1788,
1693, 1550, 1383, 1205, 1004, 745, 700; 1H NMR (600 MHz, CDCl3)
δ 7.40−7.33 (m, 5H), 5.60−5.58 (m, 1H), 5.50−5.47 (m, 1H), 4.36−
4.34 (m, 1H), 4.31−4.25 (m, 3H), 2.39−2.15 (m, 3H), 1.88−1.68 (m,
1H), 0.95−0.88 (m, 15H), 0.62−0.58 (m, 6H); 13C NMR (125 MHz,
CDCl3) δ 166.1, 153.3, 144.7, 137.0 129.2, 129.1, 126.5, 120.3, 69.9,
58.7, 41.7, 28.4, 6.7, 5.1; TLC (30% EtOAc/hexanes) Rf 0.59; HRMS
(ESI) calcd for C24H36N2O6Si+H, 477.2421; found, 477.2451.
(R)-3-((R,Z)-7-Methyl-5-(nitromethyl)-2-((triethylsilyl)oxy)oct-2-
enoyl)-4-phenyloxazolidin-2-one (3l). The title compound was
prepared according to the general procedure using imide 1 (50.0
mg, 0.150 mmol, 1.0 equiv), nitroalkene 2l28b (29.0 mg, 0.225 mmol,
1.5 equiv), and vinylmagnesium bromide (0.23 mL, 0.230 mmol, 1.5
equiv), affording 45.0 mg (62%) of the product isolated as a clear oil.
Analytical data for 3l: IR (thin film, cm−1) 2957, 2876,1787, 1693,
(R)-3-((R,Z)-5-(Thiophen-2-yl)-2-((triethylsilyl)oxy)hex-2-enoyl)-4-
phenyloxazolidin-2-one (3g). The title compound was prepared
according to the general procedure using imide 1 (50.0 mg, 0.150
mmol, 1.0 equiv), nitroalkene 2g28a (35.0 mg, 0.225 mmol, 1.5 equiv),
and vinylmagnesium bromide (0.23 mL, 0.230 mmol, 1.5 equiv),
affording 42.0 mg (54%) of the product isolated as a yellow oil.
Analytical data for 3g: IR (thin film, cm−1) 2957, 2877, 2360, 1785,
1
1695, 1379, 1204, 1013, 744, 700; H NMR (600 MHz, CDCl3) δ
7.37−7.23 (m, 6H), 6.97−6.96 (m, 1H), 6.90 (d, J = 3 Hz, 1H), 5.51−
5.46 (m, 2H), 4.72−4,69 (m, 2H), 4.61−4.59 (m, 1H), 3.99−3.92 (m,
1H), 2.66−2.63 (m, 2H), 0.93−0.90 (m, 9H), 0.64−0.60 (m, 6H); 13C
NMR (150 MHz, CDCl3) δ 166.0, 153.1, 145.0, 142.3, 137.1, 129.2
129.1, 127.1, 126.5, 125.3, 124.6, 117.3, 79.9, 69.9, 58.5, 39.0, 30.4, 6.6,
5.2; TLC (30% EtOAc/hexanes) Rf 0.36; LRMS (ESI+) calcd for
C25H32N2O6SSi+Na, 539.17; found, 539.26.
(R)-3-((R,Z)-5-(Furan-2-yl)-6-nitro-2-((triethylsilyl)oxy)hex-2-
enoyl)-4-phenyloxazolidin-2-one (3h). The title compound was
prepared according to the general procedure using imide 1 (50.0
1
1383, 1205, 745, 700; H NMR (600 MHz, CDCl3) δ 7.40−7.33 (m,
5H), 5.59 (t, J = 13.0 Hz, 1H), 4.82 (dd, J = 8.4, 7.8 Hz, 1H), 4.72 (t, J
= 9.0 Hz, 1H), 4.36−4.25 (m, 3H), 2.41−2.38 (m, 2H), 2.18−2.16 (m,
1H), 1.67−1.66 (m, 1H), 1.38−1.15 (m, 2H), 0.92−0.89 (m, 15H),
0.63−0.59 (m, 6H); 13C NMR (150 MHz, CDCl3) δ 166.1, 153.2,
144.6, 137.2, 129.2, 129.0, 126.4, 119.1, 79.1, 69.8, 58.6, 40.9, 35.5,
E
DOI: 10.1021/acs.joc.5b02693
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
27.6, 25.1, 22.7, 22.3, 6.7, 6.6, 5.2, 5.2; TLC (20% EtOAc/hexanes) Rf
0.39; HRMS (ESI+) calcd for C25H38N2O6Si+H, 491.2577; found,
491.2600.
(7) (a) Gupta, V.; Sudhir, V. S.; Mandal, T.; Schneider, C. Angew.
Chem., Int. Ed. 2012, 51, 6739−6742. (b) Basu, S.; Gupta, V.; Nickel,
J.; Schneider, C. Org. Lett. 2014, 16, 274−277.
(S)-4-Nitro-3-phenylbutanal. A 20 mL scintillation vial was
charged with 3a (35 mg, 0.069 mmol, 1.0 equiv) and CH2Cl2 (1.0 mL,
0.07 M). Ozone was bubbled through the solution at −78 °C until the
solution turned a light blue. The reaction was then purged with N2 for
15 min until the color dissipated. Dimethyl sulfide (0.08 mg, 0.135
mmol, 5.0 equiv) was added to the reaction mixture and warmed to
room temperature. Once the reaction was complete, the solution was
diluted with CH2Cl2 (5 mL) and H2O (5 mL). The layers were
separated, and the aqueous layer was extracted with methylene
chloride (3 × 5 mL). The combined organic extracts were washed with
brine (5 mL), dried with sodium sulfate, and concentrated in vacuo.
The crude mixture was purified by flash chromatography (30%
EtOAc/hexanes) to provide 13.4 mg (52%) of the product as a
(8) Gu, Y.; Wang, Y.; Yu, T.-Y.; Liang, Y.-M.; Xu, P.-F. Angew. Chem.,
Int. Ed. 2014, 53, 14128−14131.
(9) Yang, D.; Wang, L.; Han, F.; Zhao, D.; Zhang, B.; Wang, R.
Angew. Chem., Int. Ed. 2013, 52, 6739−6742.
(10) (a) Boyce, G. R.; Greszler, S. N.; Johnson, J. S.; Linghu, X.;
Malinowski, J. T.; Nicewicz, D. A.; Satterfield, A. D.; Schmitt, D. C.;
Steward, K. M. J. Org. Chem. 2012, 77, 4503−4515. (b) Boyce, G. R.;
Johnson, J. S. tert-Butyl 2-(tert-butyldimethylsilyl)-2-oxoacetate. e-
EROS Encyclopedia of Reagents for Organic Synthesis; John Wiley and
Sons Ltd., 2013.
(11) Boyce, G. R.; Johnson, J. S. Angew. Chem., Int. Ed. 2010, 49,
8930−8933.
(12) (a) Kuwajima, I.; Kato, M. J. Chem. Soc., Chem. Commun. 1979,
708−709. (b) Reich, H. J.; Olson, R. E.; Clark, M. C. J. Am. Chem. Soc.
1980, 102, 1423−1424. (c) Kuwajima, I.; Kato, M. Tetrahedron Lett.
1980, 21, 623−626. (d) Enda, J.; Matsutani, T.; Kuwajima, I.
Tetrahedron Lett. 1984, 25, 5307−5310. (e) Kato, M.; Mori, A.;
Oshino, H.; Enda, J.; Kobayashi, K.; Kuwajima, I. J. Am. Chem. Soc.
1984, 106, 1773−1778. (f) Enda, J.; Kuwajima, I. J. Am. Chem. Soc.
1985, 107, 5495−5501. (g) Matsuoka, R.; Horiguchi, Y.; Kuwajima, I.
Tetrahedron Lett. 1987, 28, 1299−1302.
1
colorless oil. H NMR spectral data matched those reported for the
title compound;24a [α]D −24 (c 0.71, CHCl3).
(S)-4-Nitro-3-phenylbutan-1-ol. A 20 mL scintillation vial was
charged with 3a (14 mg, 0.027 mmol, 1.0 equiv) and CH2Cl2 (1.0 mL,
0.03 M). Ozone was bubbled through the solution at −78 °C until the
solution turned a light blue. The reaction was then purged with N2 for
15 min until the color dissipated. NaBH4 (3.11 mg, 0.082 mmol, 3.0
equiv) was added, and the reaction was warmed to room temperature.
Once the reaction was complete, the solution was diluted with CH2Cl2
(5 mL) and H2O (5 mL). The layers were separated, and the aqueous
layer was extracted with methylene chloride (3 × 5 mL). The
combined organic extracts were washed with brine (5 mL), dried with
sodium sulfate, and concentrated in vacuo. The crude mixture was
purified by flash chromatography (30% EtOAc/hexanes) to provide 4
(13) Boyce, G. R.; Liu, S.; Johnson, J. S. Org. Lett. 2012, 14, 652−
655.
(14) Schmitt, D. C.; Johnson, J. S. Org. Lett. 2010, 12, 944−947.
(15) Nicewicz, D. A.; Johnson, J. S. J. Am. Chem. Soc. 2005, 127,
6170−6171.
(16) Satterfield, A. D. Ph.D. Thesis. University of North Carolina,
Chapel Hill, NC, 2009.
(17) Greszler, S. N.; Malinowski, J. T.; Johnson, J. S. J. Am. Chem.
Soc. 2010, 132, 17393−17395.
1
mg (75%) of the product as a colorless oil. H NMR spectral data
matched those reported for the title compound.24b SFC analysis
showed a 96:4 er for the product.
(18) (a) Yao, M.; Lu, C.-D. Org. Lett. 2011, 13, 2782−2785.
(b) Jiang, J.-L.; Yao, M.; Lu, C.-D. Org. Lett. 2014, 16, 318−321.
(19) Al-Rashid, Z. F.; Johnson, W. L.; Hsung, R. P.; Wei, Y.; Yao, P.-
Y.; Liu, R.; Zhao, K. J. Org. Chem. 2008, 73, 8780−8784.
(20) Brook, A. G. Acc. Chem. Res. 1974, 7, 77−84.
(21) Evans, D. A.; Kim, A. S. (S)-4-Benzyl-2-Oxazolidinone e-EROS
Encyclopedia of Reagents for Organic Synthesis; John Wiley and Sons
Ltd., 2001.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02693.
Copies of the 1H and 13C NMR spectra and HPLC traces
(PDF)
(22) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130,
833−835.
AUTHOR INFORMATION
(23) Nicewicz, D. A.; Bret
́ ́ ́
eche, G.; Johnson, J. S. Org. Synth. 2008,
■
85, 278−286.
Corresponding Author
*E-mail: jsj@unc.edu.
Notes
(24) The Supporting Information contains a more detailed
explanation of the stereochemical determination and enantiomeric
ratio. (a) Gotoh, H.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2007, 9,
5307−5309. (b) Palomo, C.; Landa, A.; Mielgo, A.; Oiarbide, M.;
Puente, A.; Vera, S. Angew. Chem., Int. Ed. 2007, 46, 8431−8435.
(25) Mikami, K.; Shimizu, M.; Zhang, H.-C.; Maryanoff, B. E.
Tetrahedron 2001, 57, 2917−2951.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The project described was supported by Award No. R01
GM084927 from the National Institute of General Medical
Sciences.
(26) (a) McNulty, J.; Mo, R. Chem. Commun. 1998, 933−934.
(b) Robertson, J.; Hall, M. J.; Green, S. P. Org. Biomol. Chem. 2003, 1,
3635−3638. (c) Blidi, L. E.; Assaf, Z.; Bres, F. C.; Veschambre, H.;
Thery, V.; Bolte, J.; Lemaire, M. ChemCatChem 2009, 1, 463−471.
́
(27) Alaimo, P. J.; Peters, D. W.; Arnold, J.; Bergman, R. G. J. Chem.
Educ. 2001, 78, 64.
REFERENCES
■
(1) (a) Denmark, S. E.; Heemstra, J. R.; Beutner, G. L. Angew. Chem.,
Int. Ed. 2005, 44, 4682−4698. (b) Kalesse, M.; Cordes, M.;
Symkenberg, G.; Lu, H.-H. Nat. Prod. Rep. 2014, 31, 563−594.
(2) Casiraghi, G.; Battistini, L.; Curti, C.; Rassu, G.; Zanardi, F.
Chem. Rev. 2011, 111, 3076−3154.
(3) Schneider, C.; Abels, F. Org. Biomol. Chem. 2014, 12, 3531−3543.
(4) Fukui, K.; Yonezawa, T.; Nagata, C.; Shingu, H. J. Chem. Phys.
1954, 22, 1433−1442.
(28) (a) Trost, B. M.; Muller, C. J. Am. Chem. Soc. 2008, 130, 2438−
̈
2439. (b) Sekikawa, T.; Kitaguchi, T.; Kitaura, H.; Minami, T.;
Hatanaka, Y. Org. Lett. 2015, 17, 3026−3029. (c) Guo, C.; Xue, M.-X.;
Zhu, M.-K.; Gong, L.-Z. Angew. Chem., Int. Ed. 2008, 47, 3414−3417.
(5) Bencivenni, G.; Galzerano, P.; Mazzanti, A.; Bartoli, G.;
Melchiorre, P. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 20642−20647.
(6) Albrecht, L.; Dickmeiss, G.; Weise, C. F.; Rodríguez-Escrich, C.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2012, 51, 13109−13113.
F
DOI: 10.1021/acs.joc.5b02693
J. Org. Chem. XXXX, XXX, XXX−XXX