Palladium-catalyzed diastereo- and enantioselective synthesis of substituted cyclopentanes through a dynamic kinetic asymmetric formal [3+2]-cycloaddition of vinyl cyclopropanes and alkylidene azlactones

Article abstract of DOI:10.1002/anie.201101684

An enantioselective preparation of vinylcyclopentanes has been achieved through the title reaction (see scheme). A range of aryl, heterocyclic, alkenyl, and alkyl substituted azlactone alkylidenes have been utilized, giving the cyclopentane products in go

Full text of DOI:10.1002/anie.201101684

DOI: 10.1002/anie.201101684
Asymmetric Synthesis
Palladium-Catalyzed Diastereo- and Enantioselective Synthesis of
Substituted Cyclopentanes through a Dynamic Kinetic Asymmetric
Formal [3+2]-Cycloaddition of Vinyl Cyclopropanes and Alkylidene
Azlactones**
Barry M. Trost* and Patrick J. Morris
The development of new enantioselective methods for the
formation of cyclopentane rings containing multiple stereo-
centers is of importance both in organic and medicinal
chemistry.[1] A powerful approach would be a metal-catalyzed
asymmetric formal [3+2]-cycloaddition between a 1,3-dipole
and an olefin; it would allow for the construction of the
cyclopentane and form multiple stereocenters in a single
synthetic step. Additionally, development of this method-
ology would identify new “three-carbon-atom” precursors for
asymmetric cycloadditions, beyond the relatively small
number that currently exist in the literature.[2]
propane 1a to aldehydes.[7] However, they needed to employ
an alternative strategy using chiral Lewis acid catalysts to
achieve asymmetric induction, a process that has not been
expanded to electron-poor olefins.[8,9]
Previously, the chiral ligands developed in our laboratory
(L1–L4; Scheme 2) for the Pd-catalyzed asymmetric allylic
alkylation have been employed to induce asymmetry at both
Vinyl epoxides, aziridines, and cyclopropanes bearing
electron-withdrawing groups are known to open into 1,3-
dipoles in the presence of palladium(0) catalysts. The result-
ing PdII complexes add across olefins,[3] isocyanates,[4,5]
carbodiimides,[6] and aldehydes[7] to afford five-membered
rings. We hypothesized that we could use 1,3-dipoles gen-
erated from vinyl cyclopropanes as a novel three carbon
fragment to generate cyclopentanes in an asymmetric fashion
through palladium catalysis.
Tsuji et al. have reported that vinylcyclopropane 1a adds
across methyl vinyl ketone in the presence of [Pd2dba3] (dba =
dibenzylideneacetone) and bis(diphenylphosphino)ethane to
afford vinylcyclopentane 3 (Scheme 1).[3] Later, Johnson et al.
demonstrated the Pd-catalyzed additions of the vinyl cyclo-
Scheme 2. Trost asymmetric allylic alkylation ligands.
the prochiral nucleophile and/or at the carbon of the p-allyl
which is being attacked.[10a–c] However, it has not been
demonstrated for these ligands to be able to control
stereochemistry in a bond-forming event distal to the p-allyl
Pd-complex. Our proposed Pd-catalyzed formal [3+2]-cyclo-
addition is a new challenge for these chiral ligands, in that it is
requisite for them to control the stereochemistry of the
Michael addition by the malonate carbanion, in addition to
the stereochemistry at the nucleophile and the allyl center.
To explore the prospect of this new class of asymmetric
1,3-dipole donors, we chose alkylidene azlactones as accept-
ors since these olefins should represent a reactive and useful
class that would generate an interesting family of conforma-
tionally constrained a-amino acids.[11] Promisingly, when 1a
and 4a were combined with [Pd2(dba)3]·CHCl3 (3 mol%) and
L1 (9 mol%) in toluene at room temperature, the desired
[3+2]-cycloadduct was observed, albeit in only a 16% yield
with a 10:1 d.r. and 60% ee.
Scheme 1. Palladium-catalyzed addition of vinyl cyclopropanes 1 to
electron poor olefins. EWG=electron-withdrawing group.
[*] Prof. B. M. Trost, P. J. Morris
Department of Chemistry, Stanford University
337 Campus Drive, Stanford CA 94305 (USA)
E-mail: bmtrost@stanford.edu
[**] This work has been supported by the National Science Foundation
and the National Institutes of Health (GM033049). The authors
thank Johnson Matthey for the gift of palladium salts, Dr. Allen
Oliver of Notre Dame for X-ray crystallography, and Dr. Kami Hull
for editorial assistance.
Attributing the low reactivity of the dipole 2 derived from
precursor 1a to its low lifetime, we speculated that the
trifluoroester 1b might possess sufficiently greater stability to
increase its lifetime, while at the same time maintaining
reactivity.[12] Indeed, by combining our more reactive vinyl
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101684.
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Table 1: Selected optimization results.
Table 2: Cycloaddition of vinyl cyclopropanes with aryl alkylidene
azlactones.
Entry
Ligand
Solvent
Yield
[%][a]
d.r.[b]
ee
Entry Substrate
Product
Yield d.r.[b]
[%][a]
ee
[%][c]
[%][c]
1
L1
toluene
toluene
toluene
toluene
a,a,a-trifluorotoluene
THF
CH2Cl2
64
61
66
21
69
14
77
82
19:1
19:1
15:1
4:1
4:1
15:1
8:1
96
92
À87
23
83
89
91
94
2
3
4
5
6
7
8
L2
L3
L4
L1
L1
L1
L1
1
78
19:1
98
dioxane
14:1
2
3
4
70
83
0
>19:1
93
94
[a] Yields of isolated products. [b] Diastereomeric ratios determined by
1H NMR spectroscopy. [c] Determined by chiral HPLC.
19:1
cyclopropane 1b and Michael acceptor 4a, we were able to
observe the desired product in 64% yield, 19:1 d.r., and 96%
ee (Table 1, entry 1). Notably, only two of four possible
diastereomers were observed, one of which was heavily
favored. Furthermore, the reactions proceeded well at room
temperature.
n.d. n.d.
Further ligand (Table 1, entries 2–4) and solvent optimi-
zation (Table 1, entries 5–8) confirmed that ligand L1 was
differential, and the highest selectivities were observed with
toluene. Dioxane provided higher yields at only a modest
decrease in stereoselectivity (Table 1, entry 8). We also found
the catalyst loading could be reduced from 6% to 4%.
We then sought to evaluate the scope of the reaction with
a variety of aryl-substituted azlactones, using the conditions
for optimal diastereoselectivity (Table 2). Moderately elec-
tion-withdrawing substituents in the meta- and para- positions
(entries 1–3) were well tolerated, maintaining high levels of
enantioselectivity and diastereoselectivity. However, when a
substituent was introduced in the ortho-position (entry 4), no
product was obtained, presumably due to the additional steric
bulk. The moderately electron-rich 2-naphthyl system was
also well tolerated (entry 5). A substrate bearing a highly
electron-withdrawing substituent (entry 6) proved slightly
detrimental to the enantioselectivity and diastereoselectivity,
while electron-rich furan (entry 7) gave excellent diastereo-
selectivity, enantioselectivity and yield.
Next, we examined non-aromatic substituents on the
azlactone electrophile (Table 3). The cinnamyl derivative
(entry 1) gave excellent selectivities, albeit in a slightly
reduced yield. Notably, only 1,4-addition was observed. The
n-hexyl derivative (entry 2) reacted well, affording a 63%
yield of the desired product, with somewhat reduced dia-
stereo- and enantioselectivity. Increasing the steric bulk to
cyclohexyl led to no product formation (entry 3), suggesting
sensitivity to steric effects on the electrophile, similar to the
ortho-methoxyphenyl group (Table 2, entry 4). Finally, both a
protected alcohol in the alkyl chain (entry 4) and a heter-
oatom were well tolerated, with no elimination products
observed in the latter case (entry 5). Those azlactones which
5
84
>19:1
94
6
7
72
87
8:1
85
95
>19:1
[a] Yields of isolated products. [b] Diastereomeric ratios determined by
1H NMR spectroscopy. [c] Determined by chiral HPLC.
are more reactive for steric (6b) or electronic reasons (4g),
gave reduced diastereo- and enantioselectivities, while those
with increased steric bulk (6c) or with electron donating (6a)
substituents appeared gave good selectivity but reduced (or
no) yield.
To rationalize the observed stereoselectivity, we propose a
modification of our previously reported “wall and flap”
model (Scheme 3).[10b,13] Both the matched and mismatched
ionization of the starting vinyl cyclopropane ((R)-1b, (S)-1b))
occur to give complexes 8 and 9. By p–s–p equilibration, 8
and 9 can interconvert to the thermodynamically favored 8,
where the malonate resides under the “flap” in order to avoid
the steric bulk of the “wall” in 9. The malonate anion attacks
the alkylidene azlactone, when the aryl group on the
alkylidene is oriented away from the back “wall” of the
ligand (10). Finally, attack of the azlactone anion onto the p-
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Table 3: Cycloaddition of vinyl cyclopropanes with non-aryl alkylidene
azlactones.
Scheme 4. Functionalization of cycloadduct for crystallographic analy-
Entry Substrate
Product
Yield d.r.[b]
[%][a]
ee
sis.[16]
[%][c]
solid. Single-crystal X-ray diffraction analysis secured the
relative and absolute configuration of 12.[14] Interestingly, our
method provides a trans relationship between the vinyl and
aryl groups, rather than the thermodynamically more favored
cis diastereomer.[15]
The juxtaposition of functionality allows for ready struc-
tural modification (Scheme 5). For example, treatment of 5 f
with dicyclohexyl borane in THF, followed by m-CPBA
(meta-chloroperbenzoic acid) oxidation of the trialkylborane
gives the primary alcohol in situ, which cyclizes onto the
azlactone to give lactone 13.
1
51
>19:1
94
74
2
3
4
5
63
0
8:1
n.d. n.d.
64
73
3:1[d] 77[e]
10:1
63
Scheme 5. One-step functionalization to bicyclic system.
[a] Yields of isolated product. [b] Diastereomeric ratios determined by
1H NMR spectroscopy. [c] Determined by chiral HPLC. [d] A 3:1 mixture
of the E/Z isomers of 6d was used. [e] Determined on a derivative of this
compound.
In conclusion, we have developed a new palladium-
catalyzed enantioselective formal [3+2] cycloaddition
between vinyl cyclopropanes and prochiral Michael accept-
ors. The use of the bis(2,2,2-trifluoroethyl)malonate vinyl-
cyclopropanes allows much higher yields and selectivities.
Using alkylidene azalactones as the acceptor for this reaction
provides access to highly functionalized chiral amino acid
derivatives, a method which simultaneously sets three stereo-
genic centers in excellent enantio- and diastereoselectivies.
allyl-palladium (11) provides the observed major diastereo-
mer 5a.
In order to determine the configuration of 5b, it was
treated with sodium methoxide in methanol (Scheme 4) to
afford trimethyl ester 12 in quantitative yield as a crystalline
Scheme 3. Mechanistic rationale.
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Communications
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been used to induce asymmetry in conjugate addition
reactions, as well as the first time racemic vinyl cyclopropanes
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Received: March 9, 2011
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[14] The relative and absolute configurations of the other products
are assigned by analogy to 5b.
[15] The heats of formation of 5b and epi-5b were calculated using
SPARTAN 06 Essential 1.0.1. Epi-5b was found to be
11.6 kJmolÀ1 more stable. For details, see Supporting Informa-
tion.
Published online: May 23, 2011
Keywords: asymmetric synthesis · azlactones · cycloaddition ·
.
palladium catalysis · vinyl cyclopropanes
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[16] CCDC 825686 contains the supplementary crystallographic data
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