Palladium-catalyzed diastereo- and enantioselective formal [3 + 2]-cycloadditions of substituted vinylcyclopropanes

Article abstract of DOI:10.1021/ja309003x

We describe a palladium-catalyzed diastereo- and enantioselective formal [3 + 2]-cycloaddition between substituted vinylcyclopropanes and electron-deficient olefins in the form of azlactone- and Meldrums acid alkylidenes to give highly substituted cyclopentane products. By modulation of the electronic properties of the vinylcyclopropane and the electron-deficient olefin, high levels of stereoselectivity were obtained. The remote stereoinduction afforded by the catalyst, distal from the chiral pocket generated by the ligand, is proposed to be the result of a new mechanism invoking the Curtin-Hammett principle.

Full text of DOI:10.1021/ja309003x

Article
pubs.acs.org/JACS
Palladium-Catalyzed Diastereo- and Enantioselective Formal [3 + 2]-
Cycloadditions of Substituted Vinylcyclopropanes
Barry M. Trost,* Patrick J. Morris, and Simon J. Sprague
Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States
S
* Supporting Information
ABSTRACT: We describe a palladium-catalyzed diastereo- and
enantioselective formal [3 + 2]-cycloaddition between sub-
stituted vinylcyclopropanes and electron-deficient olefins in the
form of azlactone- and Meldrum’s acid alkylidenes to give highly
substituted cyclopentane products. By modulation of the
electronic properties of the vinylcyclopropane and the
electron-deficient olefin, high levels of stereoselectivity were
obtained. The remote stereoinduction afforded by the catalyst,
distal from the chiral pocket generated by the ligand, is proposed
to be the result of a new mechanism invoking the Curtin−
Hammett principle.
the cyclopropane ring with an electron-donating group capable
of stabilizing the cation and an electron-withdrawing group for
anion stabilization; hence, so-called “donor−acceptor” cyclo-
propanes have emerged as dipole precursors.7 To date, three
main methods by which donor−acceptor cyclopropanes may be
activated to unmask the 1,3-dipole (Figure 2) have been
INTRODUCTION
■
The preparation of functionalized cyclopentane-containing
compounds from simple precursors in a stereocontrolled
fashion has received a great deal of attention from the synthetic
community in recent years.1 Methods involving [3 + 2]-
cycloaddition reactions, or reactions that may be formally
considered as such, have been featured fairly frequently in the
strategies being added to the chemical lexicon.2 Such
approaches are attractive because they satisfy a desirable
ambition of modern synthesis, that of atom economy.3
While cycloadditions of 1,3-dipoles such as azides with
unsaturated compounds may typically occur under mild
conditions,4 the generation and controlled reaction of a 1,3-
dipole for the synthesis of carbocyclic products presents a
formidable challenge. The well-established reaction of so-called
trimethylenemethane with olefins under palladium catalysis has
allowed access to a range of cyclopentane products (Figure 1),5
and in recent years has been rendered asymmetric through the
development of new classes of chiral ligands.6
Figure 2. Methods of activation of donor−acceptor cyclopropanes.
reported. In perhaps the simplest case, thermal activation can
lead to C−C bond scission to afford the dipole.8 Alternatively, a
Lewis acid may bind to the acceptor group,9 further stabilizing
the anionic charge and favoring dipole formation. This method
of activation has been expanded to the use of chiral Lewis acids,
to give high levels of enantioinduction in the synthesis of cis-
substituted tetrahydrofurans.9i Finally, low valent metals
including palladium(0),10 nickel(0),11 iron(0),12 and iridi-
um(0)13 have been used to stabilize the resulting cation
through interaction with the donor group. The interaction of
the resulting dipoles with an olefin represents a formal [3 + 2]-
cycloaddition reaction, leads to the construction of two new
C−C bonds, and results in the creation of up to four
stereocenters.
Figure 1. Trimethylenemethane addition reaction.
The addition of all-carbon 1,3-dipoles to olefins under mild
conditions requires that substrates and/or reaction conditions
are selected such that the dipole is stabilized to allow time for
the desired intermolecular reaction to take place before dipole
recombination or polymerization can occur. As such,
substituted cyclopropanes have been featured widely as dipole
precursors, with the release of strain energy providing a
thermodynamic driving force for dipole generation. Stabiliza-
tion of the dipole is generally achieved through substitution of
Received: September 10, 2012
Published: October 2, 2012
© 2012 American Chemical Society
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A subset of reactions in this latter class employs cyclo-
propanes bearing a vinyl substituent as donor group.
Interaction of the vinyl group with either palladium(0) or
nickel(0) leads to π-allyl formation with resulting cation
stabilization, with an electron-withdrawing substituent posi-
tioned to stabilize the anion.14 Tsuji and co-workers first
reported the addition reaction of vinylcyclopropane 1 with
methyl vinyl ketone 2 to give the cyclopentane product 3 in
66% yield as a mixture of diastereomers (Figure 3).10a The
Figure 5. Possible mechanisms for stereocontrol of the proposed
annulation reactions.
Figure 3. Tsuji’s palladium-catalyzed annulation of methyl vinyl
ketone.
reaction is proposed to proceed via a π-allyl-palladium
intermediate in which the dipole is stabilized long enough to
allow conjugate addition of the anion into the enone, with the
resulting enolate trapping onto the π-allyl species to complete
the cyclization with concomitant ejection of the Pd0 catalyst.
Until recently, few of the processes disclosed delivered the
desired carbocyclic products with control of absolute stereo-
chemistry; many processes were also found to give mixtures of
diastereomers. On the basis of our previous exploits in the field
of asymmetric palladium π-allyl chemistry, we wondered
whether the use of our chiral DPPBA bisphosphine ligands15
(Figure 4) might be able to create chiral space around a metal
center capable of influencing the stereoselectivity of annulation
reactions based on vinylcyclopropane substrates.
selectivity of the conjugate addition of the enolate onto
Meldrum’s acid alkylidene and the facial selectivity of the ring-
closing reaction, setting both of the resulting stereocenters.
Alternatively (pathway B), if the initial conjugate addition were
unselective (due to the remote nature of the chiral pocket
created by the ligand−metal complex) but reversible, it could
be that one of the two resulting epimeric complexes underwent
stereocontrolled ring closure more rapidly than the other, such
that overall high stereoselectivity would be obtained, in
accordance with the Curtin−Hammett principle. Given the
significant distance between the chiral pocket provided by the
ligand and the site of conjugate addition, it was anticipated that
a reaction proceeding via pathway B in which conjugate
addition is reversible would offer a greater opportunity for
enantioinduction.
To investigate the proposed transformation, Meldrum’s acid
adduct 4 was reacted with a range of vinylcyclopropanes
substituted with electron-withdrawing groups (Table 1).
Dimethylmalonyl substrate 1 was found to undergo the formal
cycloaddition process in near quantitative yield to give product
5a (entry 1), but the control over both absolute and relative
stereochemistry was found to be rather poor for the major
diastereomer, but encouraging for the minor diastereomer.
Use of the di(trifluoroethyl) ester analogue 6 (entry 2) led to
slightly improved diastereocontrol, and again gave an excellent
yield of the desired product 5b; however, the control of
absolute stereochemistry was similarly poor for the major
diastereomer but good for the minor diastereomer. In an
attempt to render the conjugate addition step more reversible,
the substituent on the vinylcyclopropane was further modified.
Switching to Meldrum’s acid derivative 7 (entry 3) gave the
corresponding product 5c with excellent diastereo- and
enantiocontrol, albeit with room for optimization in terms of
yield. Given the impressive levels of stereocontrol, in our
further studies we investigated further the use of Meldrum’s
acid-substituted vinylcyclopropane 7.
Figure 4. Chiral ligands for asymmetric palladium catalysis.
RESULTS AND DISCUSSION
■
On the basis of exploratory studies within our group, we
determined that Meldrum’s acid alkylidenes16 might prove a
suitable class of substrates, presumably due to the highly
electron-withdrawing nature of the substituents. Stereocontrol
of the proposed reaction is not so readily achieved as it might
first appear. While the DPPBA bisphosphine ligands have been
extensively used for control of nucleophilic attack onto attached
π-allyl species, they have not been widely used for more remote
stereoinduction. To achieve both diastereo- and enantiocontrol,
two possible scenarios are conceivable (Figure 5). In the first
case (pathway A), the ligand could control both the facial
Encouraged by this early result, we next brought to bear our
armory of bisphosphine ligands, with the aim of increasing the
yield to a synthetically useful level while maintaining the high
levels of stereocontrol. A screen of our four standard chiral
bisphosphine ligands identified L3 as beneficial to the yield of
the process (Table 2), without appreciable loss of diastereo- or
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a
Table 1. Screening of Various Vinylcyclopropanes
Table 3. Cycloaddition with Meldrum’s Acid Alkylidenes
a
b
1
Isolated yield. Diastereomeric ratio (d.r.) determined by H NMR.
c
Enantiomeric excess (e.e.) of major and minor diastereomers,
respectively, determined by chiral HPLC.
Table 2. Selected Optimization Results
a
b
c
entry
ligand
solvent
yield
d.r.
e.e.
1
2
3
4
5
6
7
8
9
(S,S)-L1
(S,S)-L2
(R,R)-L3
(R,R)-L4
(R,R)-L3
(R,R)-L3
(R,R)-L3
(R,R)-L3
DME
48%
27%
50%
54%
49%
26%
53%
22%
62%
5.4:1
2.2:1
6.5:1
3.2:1
6.1:1
14:1
2.7:1
24:1
17:1
−60%
−82%
87%
33%
88%
84%
30%
94%
96%
a
Yields given are of the isolated products. Diastereomeric ratios (d.r.)
DME
1
determined by H NMR. Enantiomeric excesses (e.e.) of the major
diastereomer determined by chiral HPLC.
DME
DME
THF
Thienyl-substituted cyclopentane 9f product was also prepared
with excellent stereocontrol, albeit in modest yield, whereas the
corresponding 2-furyl compound 9g was obtained in 52% yield,
as a 7:1 mixture of diastereomers and an 85% e.e. for the major
diastereomer. 2-Naphthyl-substituted cyclopentane 9h was also
prepared with excellent stereocontrol, as was enyne-derived
product 9i, which was obtained solely as the result of 1,4- rather
than 1,6-conjugate addition. The selectivity for 1,4-addition is
attributed to the steric bulk of the triisopropylsilyl group; if this
group is replaced by a methyl substituent, a mixture of products
arising from both 1,4- and 1,6-addition is obtained. Throughout
our studies, alkyl-substituted Meldrum’s acid alkylidenes were
found to be poor substrates for the reaction, as exemplified by
isopropyl-substituted cyclopentane 9j, which was formed in
only trace amount. On the other hand, the successful
preparation of the alkynyl-substituted product 9i, wherein this
substituent can be readily converted into numerous types of
alkyl group, helps to obviate this problem.
MeOH
DMF
toluene
dioxane
(R,R)-L3
a
b
Isolated yields. Diastereomeric ratio (d.r.) determined by 1H NMR.
Enationmeric excess (e.e.) of the major diastereomer, determined by
chiral HPLC.
c
enantiocontrol. A screen of solvents similarly allowed us to
select dioxane for our further studies, giving formal cyclo-
addition product 5c in 62% yield, with a 17:1 mixture of
diastereomers and a 96% e.e. for the major diastereomer.
With these conditions identified, our attention turned to
examination of the scope of the reaction. Pleasingly, we found
that a range of aryl and heteroaryl Meldrum’s acid alkylidenes
were tolerated in the reaction (Table 3), affording the
corresponding addition products in generally excellent yields
and with impressive control of both relative and absolute
stereochemistry. A variety of substituted benzaldehyde-derived
alkylidenes bearing both electron-donating and electron-
withdrawing substituents gave the corresponding cycloadducts
9a−9e in up to 78% yield, up to 17:1 d.r., and up to 96% e.e. 2-
The relative and absolute stereochemistry of cycloadduct 5c
was confirmed unambiguously by X-ray crystallography (Figure
6). The unit cell was found to contain three molecules, each
with slightly different conformation but all with the same
absolute configuration.17
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alleviated as before by π−σ−π rotation; such interconversions
may serve to enhance the enantiomeric excess of the two
diastereomers (H → C, J → E), because molecules that would
otherwise form the minor enantiomer of one diastereomer go
on to form the major enantiomer of the other diastereomer.
It proved possible to carry out chemoselective differentiation
of the two Meldrum’s acid moieties in cycloadduct 9h, to afford
further functionalized cyclopentane-containing products
(Scheme 1). In the presence of 1 equiv of sodium methoxide,
the more sterically accessible Meldrum’s acid motif was opened
to give diester 10 after treatment with TMS-diazomethane. By
contrast, if 2 equiv of sodium methoxide was employed in the
transformation, tetramethyl ester 11 was formed in good yield
after the same TMS-diazomethane treatment. Further elabo-
ration of the tetraester via a hydroboration−oxidation−
lactonization sequence afforded the highly substituted δ-lactone
12 in 40% over three steps from the tetraester 11.
Figure 6. X-ray crystal structure of addition product 5c.
The stereoconvergence of both enantiomers of starting
material to enantioenriched products can be explained by the
ability of the palladium-bound allyl species to isomerize
between η1 and η3 haptomers, so-called π−σ−π interconversion
(Figure 7).
With the formal cycloaddition of Meldrum’s acid alkylidenes
fairly rigorously explored, we sought to investigate other
dipolariphiles, which might undergo a related process to afford
further functionalized cyclopentane products.
We identified azlactone alkylidenes as possible candidate
substrates, reasoning that the cycloadducts formed would not
only contain three stereocenters over which we might be able
to exert stereocontrol, but they would also represent desirable
highly functionalized amino acid derivatives.
We were delighted to discover that the enantioselective
addition of substituted vinylcyclopropane 6 and a range of
azlactone alkylidenes 13a−o (Table 4) gave the corresponding
functionalized cyclopentane products 14a−o, generally in good
to excellent yields with control of both the relative and the
absolute stereochemistry.19
Figure 7. Explanation of π−σ−π interconversion for stereoconver-
gence.
Our chiral diphosphine ligands (Figure 4) were found to
create suitable chiral space to allow highly enantioselective
addition. A range of aryl azlactone alkylidenes performed
particularly well, although very electron-rich substituents,
exemplified by substrates 13e and 13f, were found to be either
unreactive or to deliver the desired product in low yield. By
contrast, electron-poor alkylidene 13g gave the product 14g in
good yield with good diastereo- and enantiocontrol, and
naphthyl compound 13h also performed very well. Beyond
alkylidenes substituted with aryl rings, functionalized cinnamyl
compound 14i was also prepared in good yield and impressive
stereocontrol, and heterocyclic substituents were also tolerated
on the alkylidene, as demonstrated by the reactions to form
thienyl and furyl compounds 14j and 14k. In both cases, the
degree of stereocontrol was excellent. Moving to more
challenging substrates, cyclopentane products bearing heter-
oatom substituents (14l), alkyl substituents (14m−14o) were
found to be either inaccessible under the reaction conditions
(14m) or to be formed with somewhat lower stereoselectivity
(14l, n, o).
Furthermore, the absolute configuration of the product is
what would be expected from the “wall and flap” mnemonic
(Figure 8).18 The “wall and flap” mnemonic proposes that the
two phenyl rings on each phosphine have their spatial
arrangements dictated by the diamine backbone, such that a
C2-symmetric chiral pocket is created around the metal center.
Both enantiomers of the starting vinylcyclopropane ((R)-7 and
(S)-7) undergo ionization in either a matched or a mismatched
event to give the corresponding π-allyl species A and F, which
may be interconverted via π−σ−π isomerization (Figure 7) to
favor that complex (A) in which steric clashes with the
phosphine “walls” are avoided. Attack of this palladium complex
onto Meldrum’s acid alkylidene then occurs. It may be that the
attack occurs so as to minimize interactions between the R
group and the ligand (B rather than D). Alternatively, it may be
that attack is reversible and that the relative rates of ring closure
(E and C) drive enantioinduction. This latter scenario would
seem to be the more likely for two reasons. First, as previously
described, the chiral environment of the ligand is rather too far
from the site of conjugate addition to afford a controlling
influence. Second, there is a plausible structural reason why ring
closure of complex C might be faster than that of complex E. In
the case of complex E, the sterically bulky R group is pushed
toward the bulky metal−ligand complex; in complex C, the R
group is held away. Either way, the enolate closes down onto
the π-allyl species to afford the major product 9 with the
observed stereochemistry. The intermediates en route to the
products derived from complex F (G, H, I, and J) each involve
steric clashes between the reactants and the ligand backbone
and hence are disfavored. However, the steric clashes may be
The absolute and relative stereochemistry was confirmed by
single-crystal X-ray diffraction analysis of a derivative of 4-
bromo compound 14b (Figure 9).19
As before, the degree of stereocontrol is surprising, because
the initial bond-forming process occurs some distance from the
metal−ligand complex bearing the chiral information; this
suggests that in a manner analogous to that previously
described, addition of the enolate formed by ionization of the
vinylcyclopropane into the azlactone may be reversible, and the
final stereochemistry observed may be explained by considering
which of the complexes is able to achieve ring closure most
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Figure 8. Rationalization of the observed stereochemistry in terms of the “wall and flap” mnemonic.
lactone 16 in excellent yield without trans-esterification of the
residual trifluoroethyl esters.
Scheme 1. Derivatization of Cycloadduct 9h
Buoyed by a number of highly successful results, we sought
to improve the reaction of those substrates where the reaction
was not so successful. A major challenge of the reaction is to
out-compete polymerization of the opened vinylcyclopropane,
which occurs readily20 to form insoluble material unless the
desired addition process is relatively rapid (Figure 11).
We reasoned that modification of the azlactone substituent
might allow unreactive substrates to be rendered more reactive.
Specifically, if the azlactone substituent were electron-with-
drawing, the (reversible) conjugate addition step should be
faster (preventing polymerization) and the stereodetermining
ring-closing step should be slower, and therefore potentially
more selective. Such a strategy was also considered attractive on
account of the fact that the azlactone would typically be
deprotected to reveal the corresponding amino acid following
the reaction; hence from a strategic perspective, the
substituents on its aryl ring might be considered to be
structurally unimportant.
Accordingly, a variety of differently substituted azlactone
alkylidenes were prepared and subjected to the reaction
conditions (Table 5). Initially, alkylidene 17a (R = Ph, Ar =
3,4-Cl2C6H3) was employed as an investigation of the overall
concept. Using the reaction with azlactone 13a (R = Ph, Ar =
Ph) as a benchmark, it was found that switching to a slightly
more electron-poor azlactone substituent did indeed give a
slight increase in yield without any drop in e.e. (18a).21
Attention was next switched to improving the yield of the 2-
methoxy-substituted azlactone, which had failed to deliver the
desired product 14e. 3,4-Dichlorophenyl-substituted azlactone
rapidly (Figure 10). As before, both enantiomers of the starting
vinylcyclopropane 6 undergo ionization to afford π-allyl species
(A and D), which may interconvert via π−σ−π isomerization
so as to minimize steric clashes (favoring A in this case). Attack
of the enolate into the azlactone alkylidene is then reversible,
and closure occurs under ligand control to deliver the observed
product. The particular diastereomer and enantiomer observed
may be rationalized on the basis of the ring closure event, which
leads to its formation. Structure C appears to minimize steric
repulsions in that the alkylidene substituent is held away from
the metal−ligand complex as bond formation occurs; moreover,
the phenyl substituent on the azlactone ring interacts with the
“flap” portion in the far quadrant, rather than with the “wall” (if
the other face of the azlactone enolate were to attack).
To explore the synthetic utility of the products, we sought to
use the compounds as precursors to fused cyclopentane-
lactones (Scheme 2). Pleasingly, azlactone adduct 14h was
found to react cleanly in a one-pot transformation to give δ-
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4-methoxyphenyl-substituted product 18d in excellent yield
and with impressive stereocontrol, showing a marked improve-
ment over the modest 36% yield of phenyl-substituted
azlactone derivative 14f previously obtained. Earlier studies
had demonstrated alkyl-substituted azlactones to be challenging
substrates. Specifically, cyclohexyl-substituted azlactone 13j
failed to deliver the corresponding addition product 14j. By
contrast, 3,4-dichlorophenyl-substituted azlactone 17e deliv-
ered cyclopentane 18e in 31% yield and with excellent
diastereocontrol, albeit in a modest 70% e.e.
Table 4. Scope and Limitations of the Cycloaddition of
Substituted Vinylcyclopropanes with Azlactone Alkylidenes
a
Such results vindicate the use of electron-poor azlactones as a
means for increasing the yield. Such results may be
comprehended in terms of the proposed mechanism of the
reaction. If the azlactone substituent is electron-poor, the first
addition step should be faster, allowing the desired reaction to
outcompete the polymerization of the dipole and enhancing the
reaction yield.
CONCLUSION
■
We have explored a range of diastereo- and enantioselective
formal cycloaddition reactions between substituted vinyl-
cyclopropanes and electron-deficient olefins. The formal
cycloaddition of Meldrum’s acid-substituted vinylcyclopropane
7 with a range of Meldum’s acid alkylidenes has been shown to
afford substituted cyclopentane products with excellent levels of
stereoselectivity. The stereochemistry of the major product was
verified by X-ray crystallography and was confirmed as that
predicted by the “wall and flap” mnemonic. It was
demonstrated that the two Meldrum’s acid residues could be
chemodifferentiated to give highly functionalized cyclopentane-
containing products.
Furthermore, building on our work with azlactone
alkylidenes, we have demonstrated that variation of the
azlactone substituent can be used to enhance the yield of
substrates that had been previously proven problematic,
allowing access to highly functionalized constrained amino
acid derivatives in enantioenriched form. We have validated the
utility of the DPPBA ligands for asymmetric induction, likely by
a new mechanism invoking a Curtin−Hammett process via a
1,3-dipolar palladium complex.
a
Yields given are for the isolated products. Diastereomeric ratios (d.r.)
determined by 1H NMR. Enantiomeric excesses of the major
diastereomer (e.e.) determined by chiral HPLC. *A 3:1 mixture of
E/Z isomers of azlactone alkylidene 13l was used in the reaction; the
e.e. of compound 14l was determined on a derivative of the compound
to aid separation on the chiral HPLC.
EXPERIMENTAL DETAILS
■
General Information. Glassware was oven-dried for at least 6 h at
110 °C or flame-dried prior to use. All reactions were performed under
inert atmosphere (dry nitrogen or argon) unless otherwise noted.
Analytical thin-layer chromatography was performed using 0.25 nm
coated commercial silica gel plates (EMD Chemicals, silica gel 60
F254). Silica gel flash chromatography was performed using Silicycle
silica gel (230−400 Mesh). Proton and carbon nuclear magnetic
resonance spectra (1H NMR and 13C NMR) were acquired on an
Inova-300 (300 MHz), Mercury 400 (400 MHz), or Varian Unity
Inova-500 (500 MHz) spectrometer. Chemical shifts are reported in
parts per million (ppm) relative to deuterochloroform (7.26 ppm for
1H NMR and 77.23 ppm for 13C NMR). Coupling constants (J) are
quoted in Hz to the nearest 0.5 Hz. Splitting patterns are reported as:
s, singlet; d, doublet; t, triplet; q, quartet, m, multiplet, etc. Melting
points (uncorrected) were measured using a Thomas-Hoover
Capillary Melting Point Analysis. Infrared (IR) spectra were recorded
as a thin film on NaCl plates with a Thermo Scientific Nicolet IR 100
FT-IR. Chiral HPLC analyses were performed on a Thermo
Separation Products spectra series P-100 or P-200 pump and a
UV100 detector (254 or 220 nm) using a Chiralpak IA, IB, or IC
column eluted with the indicated solvent mixture and a flow rate of 1
mL min−1. Optical rotations were measured on a Jasco DIP-1000
digital polarimeter using 5 cm cells and the sodium D line (589 nm) at
Figure 9. Assignment of absolute stereochemistry of cycloadduct 14b
by derivatization and X-ray diffraction analysis.
17b gave improved reactivity and delivered the addition
product 18b in a modest 29% yield but with excellent
stereocontrol. The use of 4-(trifluoromethyl)phenyl-substituted
azlactone 17c gave a further improved 64% yield and
maintained the excellent stereocontrol. The use of the
electron-poor azlactone 17d also allowed the preparation of
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Figure 10. Rationalization of the observed stereochemistry in terms of the “wall and flap” mnemonic.
Scheme 2. One-Pot Transformation of the Cycloaddition
Product 15h
Table 5. Variation of Azlactone Substituents To Improve
Yield of the Cyclization Products
a
Figure 11. Possible impact of variation of azlactone substituents.
ambient temperature in methylene chloride. High-resolution mass
spectra were obtained from Stanford University using positive
electrospray ionization (ESI+). Dioxane and toluene were distilled
from sodium metal under nitrogen prior to use.
a
Yields given are for the isolated products. Diastereomeric ratios (d.r.)
determined by 1H NMR. Enantiomeric excesses of the major
diastereomer (e.e.) determined by chiral HPLC.
Synthesis of 5c. An oven-dried reaction tube equipped with a stir
bar was charged with palladium dibenzylideneacetone−chloroform
complex (4.0 mg, 0.004 mmol) and (R,R)-L3 chiral ligand (8.0 mg,
0.010 mmol). A second reaction tube, also equipped with a stir bar,
was charged with 6,6-dimethyl-1-vinyl-5,7-dioxaspiro[2.5]octane-4,8-
dione 7 (35.0 mg, 0.178 mmol) and 5-(4-methoxybenzylidene)-2,2-
dimethyl-1,3-dioxane-4,6-dione 4 (60.0 mg, 0.229 mmol). Both tubes
were sealed with a septum, evacuated, and backfilled with dry nitrogen.
Dioxane (degassed by sparging with nitrogen for 30 min) was added to
the first tube (1 mL) and second tube (2 mL), and the tubes were
stirred for 20 min. The contents of the first reaction tube were
transferred to the second test tube via syringe, and the mixture was
stirred at room temperature for 16 h. The reaction mixture was poured
into saturated aqueous sodium bicarbonate solution, and extracted
with methylene chloride. The combined organic extracts were dried
(MgSO4) and the solvent was removed in vacuo to give the crude
product, which was purified by flash column chromatography (30−
35% diethyl ether in petroleum ether) to give the title compound 5c as
a white solid (50.8 mg, 0.111 mmol, 62%), as a 17:1 mixture of
diastereomers (by crude 1H NMR), and with a 96% e.e. for the major
diastereomer (by chiral HPLC, Chiralpak IC column, 0.7% ethanol,
27% methylene chloride, 72.3% heptanes, UV wavelength 254 nm;
retention times: 7.83 min (minor enantiomer, major diastereomer),
10.07 min (minor diastereomer), 10.60 min (minor diastereomer),
1
12.54 min (major enantiomer, major diastereomer)). H NMR (500
MHz, CDCl3): δ = 7.26 (d, J = 6.5 Hz, 2H), 6.81 (d, J = 6.5 Hz, 2H),
5.80 (ddd, J = 17.5, 10.5, 8.5 Hz, 1H), 5.35 (d, J = 17.5 Hz, 1H), 5.23
(d, J = 10.5 Hz, 1H), 4.94 (ddd, J = 13.0, 8.5, 6.0 Hz, 1H), 4.86 (s,
1H), 3.78 (s, 3H), 3.19 (dd, J = 13.0, 12.5 Hz, 1H), 2.47 (dd, J = 12.5,
6.0 Hz, 1H), 1.63 (s, 3H), 1.57 (s, 3H), 1.19 (s, 3H), 0.92 (s, 3H). 13C
NMR (125 MHz, CDCl3): δ = 170.4, 170.1, 167.1, 166.6, 160.6, 133.9,
132.9, 125.0, 121.2, 114.6, 105.6, 105.3, 66.2, 64.7, 62.1, 56.2, 55.5,
42.2, 29.6, 29.4, 29.3, 28.5. IR (cm−1): 3583, 3001, 2944, 1769, 1746,
1609, 1514, 1393, 1382, 1275, 1205, 1186, 1091, 1029, 929, 732.
HRMS (ESI+) observed 481.1468; calculated 481.1479 (C24H26NaO9
[M + Na]+); [α]23 = +27.55° (c = 1.0, CH2Cl2); mp 148 °C
D
(decomposes).
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Synthesis of 14a. An oven-dried reaction tube equipped with a stir
bar was charged with palladium dibenzylideneacetone−chloroform
complex (4 mg, 0.004 mmol) and (S,S)-L1 chiral ligand (8 mg, 0.010
mmol). A second reaction tube, also equipped with a stir bar, was
charged with bis(2,2,2-trifluoroethyl) 2-vinylcyclopropane-1,1-dicar-
boxylate (40 mg, 0.12 mmol) and (Z)-4-benzylidene-2-phenyloxazol-
5(4H)-one 13a (40 mg, 0.160 mmol). Both tubes were sealed with a
septum, evacuated, and backfilled with dry nitrogen. Toluene
(degassed by sparging with nitrogen for 30 min, 1 mL) was added
to each tube, and the tubes were for stirred 20 min. The contents of
the first reaction tube were transferred to the second test tube via
syringe, and the mixture was stirred at room temperature for 16 h. The
solvent was removed in vacuo to give the crude product, which was
purified by flash column chromatography (5−10% diethyl ether in
petroleum ether) to give the title compound 14a as a colorless oil (45
mg, 0.079 mmol, 66%), as a 19:1 mixture of diastereomers (by crude
1H NMR), and with a 96% e.e. for the major diastereomer (by chiral
HPLC, Chiralpak OD-H column, 5% isopropanol, 95% heptanes, UV
wavelength 254 nm; retention times: 5.74 min (major enantiomer),
(3) Trost, B. M. Science 1991, 254, 1471−1477.
(4) For a review of asymmetric 1,3-dipolar cycloadditions, see:
Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863−909.
(5) For an early review of the use of trimethylenemethane, see: Trost,
B. M. Angew. Chem., Int. Ed. Engl. 1986, 25, 1−20.
(6) (a) Trost, B. M.; Lam, T. M. J. Am. Chem. Soc. 2012, 134,
11319−11321. (b) Trost, B. M.; Bringley, D. A.; Silverman, S. M. J.
Am. Chem. Soc. 2011, 133, 19483−19497. (c) Trost, B. M.; Silverman,
S. M. J. Am. Chem. Soc. 2010, 132, 8238−8240. (d) Trost, B. M.;
Silverman, S. M.; Stambuli, J. P. J. Am. Chem. Soc. 2007, 129, 12398−
12399. (e) Trost, B. M.; Cramer, N.; Silverman, S. M. J. Am. Chem.
Soc. 2007, 129, 12396−12397. (f) Trost, B. M.; Stambuli, J. P.;
Silverman, S. M. J. Am. Chem. Soc. 2006, 128, 13328−13329.
(7) For recent reviews on donor−acceptor cyclopropanes and their
use in transition metal chemistry and total synthesis, see: (a) Reissig,
H. U.; Zimmer, R. Chem. Rev. 2003, 103, 1151−1196. (b) Yu, M.;
Pagenkopf, B. L. Tetrahedron 2005, 61, 321−347. (c) Rubin, M.;
Rubina, M.; Gevorgyan, V. Chem. Rev. 2007, 107, 3117−3179.
(d) Carson, C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38, 3051−3060.
(e) Lebold, T. P.; Kerr, M. A. Pure Appl. Chem. 2010, 82, 1797−1812.
(f) De Simone, F.; Waser, J. Synthesis 2009, 20, 3353−3374.
(8) For selected examples, see: (a) Danishefsky, S.; Rovnyak, G. J.
Org. Chem. 1975, 40, 114−115. (b) Berkowitz, W. F.; Grenetz, S. C. J.
Org. Chem. 1976, 41, 10−13. (c) More recently, photocatalysis has
also been used to achieve formal [3 + 2]-cycloaddition of donor−
acceptor cyclopropanes using [Ru(bpz)3](PF6)2·2H2O: Maity, S.; Zhu,
M.; Shinabery, R. S.; Zheng, N. Angew. Chem., Int. Ed. 2012, 51, 222−
226 (for a related example using a photocatalyst in conjunction with a
Lewis acid, see ref 9j).
1
7.30 min (minor enantiomer)). H NMR (500 MHz, CDCl3): δ =
7.89 (dd, J = 8.5, 1.5 Hz, 2H), 7.54 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 8.0
Hz, 2H), 7.36 (m, 2H), 7.22 (m, 3H), 5.79 (ddd, J = 17.5, 10.5, 8.0
Hz, 1H), 5.23 (d, J = 17.5 Hz, 1H), 5.21 (d, J = 10.5 Hz, 1H), 4.78 (s,
1H), 4.66 (dq, J = 12.5, 8.0 Hz, 1H), 4.43 (dq, J = 12.5, 8.0 Hz, 1H),
4.40 (dq, J = 12.5, 8.0 Hz, 1H), 3.66 (ddd, J = 9.5, 8.0, 6.5 Hz, 1H),
3.41 (dq, J = 12.5, 8.0 Hz, 1H), 3.19 (dd, J = 13.5, 6.5 Hz, 1H), 2.51
(dd, J = 13.5, 9.5 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ = 178.6,
169.1, 168.1, 160.3, 136.4, 134.0, 133.3, 133.1, 131.2, 128.9, 128.3,
128.1, 125.7, 122.7 (q, JC−F = 276 Hz), 122.4 (q, JC−F = 276 Hz),
120.5, 91.2, 80.3, 78.6, 65.1, 61.7 (q, JC−F = 36 Hz), 61.5 (q, JC−F = 37
Hz), 58.1, 53.4, 38.0. 19F NMR (376 MHz, CDCl3): δ = −74.20 to
−74.24 (m, 3F), −74.30 to −74.35 (m, 3F). IR (cm−1): 2965, 1812,
1752, 1652, 1495, 1451, 1413, 1283, 1236, 1168, 871, 697. HRMS
(ESI+): observed 570.1336; calculated 570.1351 (C27H22F6NO6 [M +
(9) Selected examples of the use of Lewis acids to activate donor−
acceptor cyclopropanes for carbocycle synthesis, TiCl4: (a) Saigo, K.;
Shimada, S.; Shibasaki, T.; Hasegawa, M. Chem. Lett. 1990, 1093−
1096. (b) Yadav, V. K.; Sriramurthy, V. Angew. Chem., Int. Ed. 2004,
43, 2669−2671. SnCl4: (c) Komatsu, M.; Suehiro, I.; Horiguchi, Y.;
Kuwajima, I. Synlett 1991, 771−773. (d) de Nanteuil, F.; Waser, J.
Angew. Chem., Int. Ed. 2011, 50, 12075−12079. Me2AlCl:
(e) Horiguchi, Y.; Suehiro, I.; Sasaki, A.; Kuwajima, I. Tetrahedron
Lett. 1993, 34, 6077−6080. EtAlCl2: (f) Beal, R. B.; Dombroski, M.
A.; Snider, B. B. J. Org. Chem. 1986, 51, 4391−4399. TMSOTf:
(g) Sugita, Y.; Kawai, K.; Osoya, H.; Yokoe, I. Heterocycles 1999, 51,
2029−2033. Yt(OTf)3: (h) England, D. B.; Kuss, T. D. O.; Keddy, R.
G.; Kerr, M. A. J. Org. Chem. 2001, 66, 4704−4709. Enantioselective
using MgBr2: (i) Parsons, A. T.; Johnson, J. S. J. Am. Chem. Soc. 2009,
131, 3122−3123. Photocatalytic using Ru(bpy)3Cl2 and stoichio-
metric La(OTf)3 as Lewis acid: (j) Lu, Z.; Shen, M.; Yoon, T. J. Am.
Chem. Soc. 2011, 133, 1162−1164.
H]+); [α]23 = +15.61° (c = 1.0, CH2Cl2).
D
ASSOCIATED CONTENT
* Supporting Information
■
S
Full experimental procedures and spectral data for all new
compounds, as well as crystallographic data for cycloadducts 5c
and derivative 15. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
bmtrost@stanford.edu
■
(10) (a) Shimizu, I.; Ohashi, Y.; Tsuji, J. Tetrahedron Lett. 1982, 23,
3825−3828. (b) Parsons, A. T.; Campbell, M. J.; Johnson, J. S. Org.
Lett. 2008, 10, 2541−2544.
Notes
The authors declare no competing financial interest.
(11) (a) For an elegant example of the use of nickel(0) catalysis in
an enantiospecific synthesis of dihydrofurans from vinylcyclopropanes,
see: Bowman, R. K.; Johnson, J. S. Org. Lett. 2006, 8, 573−576. (b)
For a highly diastereoselective nickel-catalyzed reaction of donor−
acceptor cyclopropanes with enones and enals, see: Liu, L.;
Montgomery, J. J. Am. Chem. Soc. 2006, 128, 5348−5349.
ACKNOWLEDGMENTS
■
This work has been supported by the National Science
Foundation and the National Institutes of Health
(GM033049). AstraZeneca, the US−UK Fulbright Commis-
sion, and the Lindemann Trust are gratefully acknowledged for
funding (to S.J.S.). We also thank Johnson Matthey for the gift
of palladium salts and Dr. Allen Oliver of Notre Dame
University for X-ray crystallography.
(12) Dieskau, A. P.; Holzwarth, M. S.; Plietker, B. J. Am. Chem. Soc.
2012, 134, 5048−5051.
(13) Moran, J.; Smith, A. G.; Carris, R. M.; Johnson, J. S.; Krische, M.
J. J. Am. Chem. Soc. 2011, 133, 18618−18621.
(14) Yu and co-workers have invoked a π-allyl-Rh intermediate in the
intramolecular formal [3 + 2]-cycloaddition reaction of (nondonor−
acceptor) vinylcyclopropanes with alkenes, alkynes and allenes, see:
(a) Jiao, L.; Lin, M.; Zhuo, L.-G.; Yu, Z.-X. Org. Lett. 2010, 12, 2528−
2531. (b) Jiao, L.; Lin, M.; Yu, Z.-X. Chem. Commun. 2010, 46, 1059−
1061. (c) Li, Q.; Jiang, Q.-J.; Jiao, L.; Yu, Z.-X. Org. Lett. 2010, 12,
1332−1335. (d) Jiao, L.; Ye, S.; Yu, Z.-X. J. Am. Chem. Soc. 2008, 131,
7178−7179.
REFERENCES
■
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17830
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(16) For a convenient synthesis of Meldrum’s acid alkylidenes, see:
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(17) See the Supporting Information for full details of the X-ray
crystal structure, including full details of the unit cell. It was not
possible to unambiguously assign the absolute stereochemistry of the
minor diastereomer, although this is in part testament to the highly
diastereoselective nature of the reaction. On the basis of the “wall and
flap” mnemonic, it seems plausible that 1-epi-9 (see Figure 8) is the
major enantiomer of the minor diastereomer, although this cannot be
verified at the present time.
(18) (a) Trost, B. M.; Machacek, M. R.; Aponick, A. Acc. Chem. Res.
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4748−4750.
(21) The corresponding 4-methoxyphenyl-substituted azlactone
alkylidene (X = OMe) gave no reaction.
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