Catalytic asymmetric synthesis of spirocyclic azlactones by a double Michael-addition approach

Article abstract of DOI:10.1002/chem.201300224

Spirocyclic azlactones are shown to be useful precursors of cyclic quaternary amino acids, such as the constrained cyclohexane analogues of phenylalanine. These compounds are of interest as building blocks for the synthesis of artificial peptide analogues with controlled folds in the peptide backbone. They were prepared in the present study by a step- and atom-economic catalytic asymmetric tandem approach, requiring two steps starting from N-benzoyl glycine and divinylketones. The key of this protocol is the enantioselective formation of the azlactone spirocycles, which involves a Pd^II-catalyzed double 1,4-addition of an in situ generated azlactone intermediate to the dienone (a formal [5+1] cycloaddition). As the catalyst, a planar chiral ferrocene bispalladacycle was used. Mechanistic studies suggest a monometallic reaction pathway. Although the diastereoselectivity was found to be moderate, the enantioselectivity is usually high for the formation of the azlactone spirocycles, which contain up to three contiguous stereocenters. Spectroscopic studies have shown that the spirocycles often prefer a twist over a chair conformation of the cyclohexanone moiety. A formal [5+1] cycloaddition of divinylketones and an in situ-generated glycine-derived azlactone was catalyzed by a chiral bis-palladacycle and provided highly enantioenriched, spirocyclic, masked amino acid products. The latter were used to synthesize biologically interesting constrained cyclohexane analogues of phenylalanine in just two steps (see scheme). Copyright

Full text of DOI:10.1002/chem.201300224

DOI: 10.1002/chem.201300224
Catalytic Asymmetric Synthesis of Spirocyclic Azlactones by a Double
Michael-Addition Approach
Manuel Weber, Wolfgang Frey, and Renꢀ Peters*[a]
Abstract: Spirocyclic azlactones are
shown to be useful precursors of cyclic
quaternary amino acids, such as the
constrained cyclohexane analogues of
phenylalanine. These compounds are
of interest as building blocks for the
synthesis of artificial peptide analogues
with controlled folds in the peptide
backbone. They were prepared in the
present study by a step- and atom-eco-
nomic catalytic asymmetric tandem ap-
proach, requiring two steps starting
from N-benzoyl glycine and divinyl-
G
ferrocene bispalladacycle was used.
Mechanistic studies suggest a mono-
AHCTUNGTRENNmGUN etallic reaction pathway. Although
the diastereoselectivity was found to be
moderate, the enantioselectivity is usu-
ally high for the formation of the azlac-
tone spirocycles, which contain up to
three contiguous stereocenters. Spec-
troscopic studies have shown that the
spirocycles often prefer a twist over a
chair conformation of the cyclohexa-
none moiety.
Introduction
cycles (3-oxa-1-azaspiroACTHGNUTERNNU[G 4.5]dec-1-ene-4,8-diones), which
proceeds through a double Michael addition of an achiral
glycine-derived azlactone to symmetric and unsymmetric di-
vinylketones. In this approach, which generates up to three
contiguous stereocenters (one of which is quaternary),[8] the
azlactone pronucleophile can be formed in situ from N-ben-
zoyl glycine. Furthermore, we demonstrate the synthetic
utility of the reaction products for the formation of cyclic
quaternary amino acids.
Azlactones have found frequent applications as substrates
in asymmetric catalysis[9,10] for a diversity-oriented entrance
to a,a-disubstituted a-amino acid derivatives, owing to the
presence of orthogonal nucleophilic and electrophilic reac-
tive sites in the heterocyclic systems.[9] Catalytic asymmetric
1,4-additions[11] of azlactones to various classes of Michael
acceptors, which proceed with high levels of enantioselectiv-
ity, have recently been reported.[12] We have recently de-
Spirocycles represent a frequently found structural motif in
natural products and pharmacologically interesting com-
pounds. Their stereoselective access has therefore been in-
tensively investigated by exploring a variety of different
strategies.[1] In 2010 we reported the first example to obtain
a chiral highly enantioenriched spirocycle by a catalytic
asymmetric double 1,4-addition of a cyclic methylene-con-
taining pronucleophile (in our case a glycine-derived azlac-
tone) to a divinylketone.[2] After our initial report, a number
of complementary catalytic asymmetric double 1,4-additions
providing enantioselective access to various cyclohexanone
systems have been reported.[3,4] Although these catalytic
asymmetric methodologies have only very recently been
available, nonenantioselective versions for these stepwise
formal [5+1] cycloadditions have been known for a long
time, the first example apparently dating back to 1924 for
the formation of functionalized cyclohexanones (although in
that case, lacking a spirocyclic motif).[5,6]
AHCTUNGTREGsNNUN cribed the first catalytic asymmetric conjugate additions of
azlactones to enones.[13] In this context we have also report-
ed the first catalytic asymmetric examples, in which the
azlactone substrates have been formed in situ from racemic
acylated or unprotected amino acids.[13]
In this paper, we give a detailed account on the develop-
ment of the catalytic asymmetric tandem reaction[7] to pre-
pare highly enantioenriched azlactone/cyclohexanone spiro-
Results and Discussion
[a] M. Weber, Dr. W. Frey, Prof. Dr. R. Peters
Institut fꢀr Organische Chemie
Universitꢁt Stuttgart
Catalytic investigations: As part of our program to study co-
operative effects in asymmetric catalysis,[14] we have investi-
gated a planar chiral ferrocene bisimidazoline bispalladacy-
cle (FBIP, prepared in four steps from ferrocene), which has
recently been developed and studied in our research group
for various bimetal-catalyzed applications.[15–18] For catalytic
Pfaffenwaldring 55
70569 Stuttgart (Germany)
Fax : (+49)711-685-54330
E-mail: rene.peters@oc.uni-stuttgart.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300224.
8342
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Chem. Eur. J. 2013, 19, 8342 – 8351

FULL PAPER
Table 1. Optimization of the model reaction to form 3a by using a
double 1,4-addition of azlactone 1 generated in situ from N-benzoylated
glycine 4 to dienone 2a.
À
Figure 1. The dimeric precatalyst [FBIP Cl]2 and the monomeric activat-
Entry
x
y
Yield
Yield
ee
À
ed catalyst species FBIP X generated by treatment of the precatalyst
cis-3a [%][a]
trans-3a [%][a]
trans-3a [%][b]
with AgX/MeCN.
1
2
3
4
5
6
7
8
9
2
2
2
2
2
2
–
4
6
0.1
–
0.5
1.0
1.5
2
2
2
2
1
4
6
11
14
18
1
18
17
1
36
42
44
58
73
82
10
82
82
83
78
86
91
91
94
–
À
activity the dimeric precatalyst [FBIP Cl]2 (Figure 1) usual-
ly has to be activated by replacing the bridging chloride li-
gands. This is achieved by utilizing acetonitrile complexes of
silver salts AgX to generate monomeric catalyst species
À
[15b,d]
96
97
À
FBIP X (X =anionic ligand).
To establish a proof of principle for the formation of spi-
rocyclic azlactones through a formal [5+1] cycloaddition, we
initially treated the isolated glycine-derived azlactone 1 with
dibenzylidene acetone (2a, dba). By using conditions similar
to those used in the 1,4-addition reactions with simple
enones (AcOH/Ac2O (70:30) as the solvent mixture,
NaOAc as a base), product 3a was formed in a promising
yield and with excellent enantioselectivity (Scheme 1).
[a] Determined by using H NMR spectroscopy with mesitylene as the in-
ternal standard. [b] Determined by using HPLC analysis.
absence of the PdII catalyst, only a small product amount
was formed (Table 1, entry 7) favoring the trans isomer.
The optimized reaction conditions were then applied to
various symmetric and unsymmetric dienones on a prepara-
tive scale (Table 2).[19] With model dienone 2a (R1 =R2 =
Ph), the trans isomer was isolated in good yield (85%) and
in a highly enantiomerically enriched form (95% ee, Table 2,
entry 1). Electron donors in the para position of the aromat-
ic substituents (methyl, methoxy) resulted in good trans se-
lectivity and the trans isomers were again formed in good
yields with high enantioselectivity (entries 2 and 3). para-
Bromo and ortho-chloro substituents resulted in lower prod-
uct yields (entries 4 and 5). In case of the p-Br substituents,
the trans/cis diastereoselectivity was considerably reduced,
whereas the enantioselectivity was maintained to a high
level. In contrast, the ortho-chloro substituents in 2e result-
ed in excellent trans selectivity as only the trans isomer
could be detected, but the enantioselectivity was only mod-
erate in that case. The dialkyl-substituted substrate 2 f was
not well-tolerated (entry 6), since both the trans/cis ratio
and the product yield were poor, whereas at least the enan-
tioselectivity was useful.
With unsymmetrical dienones, the stereochemical situa-
tion is further complicated, because eight stereoisomers can
in principal be formed: enantiomeric pairs of two different
trans diastereomers and of two different cis diastereomers.
In all investigated cases the trans diastereomers were
formed in excess, sometimes almost exclusively (Table 2,
entry 10). Regarding the two possible cis diastereomers,
only one of them has been detected in nearly all cases,[20]
whereas the other one is obviously not formed in significant
amounts. In those reactions employing an unsymmetrical di-
enone, in which a cis diastereomer has been detected, it has
been formed in nearly racemic form. In contrast, both possi-
ble trans-diastereomers have been formed in similar quanti-
Scheme 1. Tandem double Michael addition to form the spirocyclic prod-
uct 3a.
To increase the step economy and operational simplicity,
we were then interested to form the azlactone substrate 1 in
situ by starting from N-benzoylated glycine 4 (Table 1). The
conditions developed for N-benzoylated tertiary amino
acids[2] (i.e., 2 mol% [FBIP Cl]2, 8 mol% AgOTf/MeCN,
À
10 mol% NaOAc) gave the chiral trans diastereomer with a
good enantiomeric excess (ee) of 83%, yet in a moderate
yield of only 36% (Table 1, entry 1). In the absence of
NaOAc, trans-3a was formed with a comparable yield, but
the enantioselectivity was somewhat reduced (Table 1,
entry 2). By using stoichiometric or excess amounts of
NaOAc the undesired achiral cis-3a product was also
formed in significant amounts (Table 1, entries 4–6), but on
the other hand, both the yield and enantiomeric excess of
trans-3a also increased with higher NaOAc loadings. In gen-
eral, relatively high concentrations have been required for
sufficiently fast product formation. Higher precatalyst load-
ings than 2 mol% revealed only a small influence on both
yield and enantioselectivity (Table 1, entries 8 and 9). In the
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8343

R. Peters et al.
Table 2. Tandem approach featuring two consecutive Michael additions as key steps to form spirocyclic prod-
ucts 3.
adopts a chairlike conformation
(Figure 2, bottom, left), in
which the phenyl substituent
and the azlactone
N atom
adopt a trans-diaxial position.
The alternative chair conformer
with an axial azlactone carbonyl
moiety (after ring inversion) is
expected to be energetically
less-favorable due to a more
severe 1,3-diaxial interaction as
a consequence of the enhanced
steric demand of the carbonyl
group relative to the azlactone
N atom. Chairlike conformers
were also noticed for trans-3d
and -3e (Figure 2).
Entry
2
3
R1
R2
trans/cis
Yield
d.r.
ee
trans-3 [%][a]
trans-3[b]
trans-3[c]
[d]
1
a
b
c
d
e
f
g
h
i
a
b
c
d
e
f
g
h
i
Ph
Ph
89:11
92:8
93:7
85
89
78
43
44
23
73
82
73
78
13
52
79
–
–
–
–
–
–
95
91
96
91
63
81
2[e,f]
3[e]
4[f]
5[f]
6
4-MeO-C6H4
4-Me-C6H4
4-Br-C6H4
2-Cl-C6H4
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeO-C6H4
4-Me-C6H4
4-Br-C6H4
2-Cl-C6H4
Me
4-MeO-C6H4
4-Me-C6H4
4-Br-C6H4
2-Cl-C6H4
4-NC-C6H4
4-O2N-C6H4
2-furyl
[d]
[d]
[d]
75:25
> 100:1
62:38
83:17
91:9
88:12
>100:1
n.d.
[d]
[d]
7
8
57:43
57:43
50:50
60:40
73:27
67:33
65:35
77/>98[g]
99/93[g]
92/93[g]
81/47[g]
88/86[g]
94/91[g]
98/95[g]
9[f]
10
11[f]
12[f]
13
The absolute configuration of
the minor diastereomer of
trans-3l could also be deter-
j
k
l
j
k
l
76:24
88:12
mined
(Figure 3).[23]
The
m
m
5R,6S,10S configuration reveals
that only the configuration at
[a] Yield of the isolated product. [b] Diastereomeric ratio of two trans isomers determined by 1H NMR spec-
troscopic analysis of the isolated product. [c] Determined by HPLC analysis. [d] Only one trans diastereomer
is possible with symmetric dienone substrates 2. [e] Reaction at 558C. [f] One equivalent of the dienone was the spirocenter is inverted rela-
used. [g] ee values of the major and minor trans isomers, respectively.
tive to (5S,6S,10S)-3j. By using
an unsymmetrical dienone, the
ties with unsymmetrical dienones and the enantioselectivity
is usually high for both of them. Good yields of the trans
isomers have been obtained for unsymmetrical dienones car-
rying a s donor (entry 8), a p donor (entry 7), a s acceptor
(entries 9 and 10), or an electron-rich heterocycle (entry 13).
Moderate or poor yields were obtained for dienone sub-
strates equipped with a p acceptor (entries 11 and 12).
catalyst system used is thus not capable of setting up the
configuration of the spirocenter with a high level of stereo-
control.
The conformational behavior in solution was studied by
1H NMR spectroscopy for compounds 3. In a chairlike con-
formation of a trans-1,3-disubstituted cyclohexanone moiety
only one 1,3-trans-diaxial proton–proton coupling can be ob-
served, whereas in a twistlike conformation two of them are
present. The average coupling constants for 1,3-trans-diaxial
Stereochemistry: Compared with the major products ob-
tained from simple enones (see ref. [13]), the configuration
is surprisingly inverted at the b-positions to the keto group,
as revealed by the X-ray single-crystal structure analysis of
trans-3j (major diastereomer and enantiomer), which pos-
sesses an S,S,S configuration (Figure 2, top).[21,22] Additional
X-ray crystal structure analyses of trans-3a, trans-3d, trans-
3e, and trans-3l (major isomer) confirm the preferred trans
configuration of the cyclohexanone rings with regard to the
two dienone b-substituents (Figure 2). The S configuration
of the stereocenters in the b-position to the keto group has
also been confirmed by chemical correlation for trans-3a
(see below in the subchapter “azlactone derivatization”). A
stereochemical consequence of the symmetric constitution
of trans-3a is that the spirocenter is not a stereocenter in
that case.
3
couplings usually range from J=10 to 15 Hz, whereas the
other vicinal 3J couplings are usually between 2 to 5 Hz,
both depending on the dihedral angle.[24] It should be noted
that in NMR spectroscopic experiments, usually only the
average of these couplings can be measured for equilibrium
mixtures of conformers, meaning that “mixed” coupling con-
stants are observed. For the preference of a chairlike confor-
mation of trans-1,3-disubstituted cyclohexanones in solution,
the observed coupling constants for the vicinal couplings are
consequently lower than for the preference of a twistlike
conformation. For the proton on C10 of trans-3a (see
3
Figure 4 with R1 =R2 =Ph), J couplings of 8.5 and 5.1 Hz
3
are observed, whereas for the proton on C6 J values of 12.3
and 4.4 Hz are measured. That means there is arguably one
1,3-trans-diaxial interaction and one “mixed” coupling,
pointing to a mixture of both chair and twist conformers.
The existence of significant amounts of the twist conformer
in solution is also supported by a relatively strong nuclear
Overhauser effect (NOE) signal between the proton on C10
and the axial proton on C7, for which the distance is consid-
erably shorter in the twist conformation (2.64 ꢃ in the crys-
tal structure of trans-3a (R=Ph, twist conformer) versus
Different conformers are preferred in the solid state de-
pending on the dienone substitution patterns. In trans-3a
and the major diastereomer of trans-3j, a twist conformation
of the cyclohexanone core is found that accommodates both
aryl rings in equatorial positions.
On the contrary, the major isomer of trans-3l carrying one
phenyl group plus a para-nitro-substituted phenyl ring
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Catalytic Asymmetric Synthesis
FULL PAPER
adopt an axial position. In con-
trast, for compounds cis-3, the
chairlike conformation (see also
Figure 6) is strongly preferred,
because both substituents can
be accommodated in equatorial
positions.
For the ortho-chlorophenyl-
substituted derivative trans-3j,
the coupling constants have
been determined at tempera-
tures from 243 to 313 K. The
couplings of the proton on C10
vary relatively strongly with the
temperature, whereas the cou-
plings of the proton on C6 are
relatively uniform (Figure 5).
The HC10–HC9b coupling con-
Figure 3. X-ray crystal struc-
ture analysis of the minor dia-
stereomer of trans-3l revealing
a 5R,6S,10S configuration.
Figure 4. Schematic representation of the chair and the twist conforma-
tion of the spirocycles trans-3.
Figure 2. X-ray crystal structure analyses of spirocyclic azlactones 3. De-
termination of the S,S,S configuration of trans-3j (major isomer, top,
twist conformation) and the relative configuration of trans-3a (middle,
left, twist conformation), trans-3d (middle right, chair conformation),
trans-3l (major isomer, bottom, left, chair conformation), and trans-3e
(bottom right, chair conformation).
Figure 5. Temperature dependence for selected coupling constants in the
spirocycle trans-3j. HC6–HC7b
(
), HC10–HC9b ), HC10–HC9a ), HC6–HC7a
( (
~
^
*
&
( ).
À
4.11 ꢃ in the crystal structure of trans-3l (R=4-O2N C6H4,
chair conformer)). However, as judged by the relatively low
coupling constant (3J=8.5 Hz) both conformers are arguably
present in comparable amounts in this mixture. Similar ob-
servations have also been made for most trans-3-derivatives,
in which no signal overlaying hampered the analysis.
stant steadily rises with increasing temperature, whereas the
HC10–HC9a coupling constant decreases. Based on the Kar-
plus curve, this indicates that the dihedral angle decreases
between HC10 and HC9a and also between HC10 and HC9b. In
the X-ray crystal structure of trans-3a, adopting the twist
conformation, dihedral angles of 177.0 (HC10–HC9a) and 65.08
(HC10–HC9b) have been determined. In the chair conforma-
tion of 3l, dihedral angles of 74.6 (HC10–HC9a) and 41.78
(HC10–HC9b) have been determined. Upon warming, both di-
hedral angles of the HC10/HC9 protons decrease, thus indicat-
ing an increasing amount of the chairlike conformation at
higher temperatures. The free enthalpy of the twist conform-
Typically, twist conformations are about 5 kcalmolÀ1
higher in energy than the corresponding chair conforma-
tions,[25] but the possibility in a twist conformation to accom-
modate both cyclohexanone residues R1 and R2 of com-
pounds trans-3 in the favorable equatorial positions appa-
rently lowers the relative energy of the twist conformers, be-
cause in the chair conformation one substituent needs to
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8345

R. Peters et al.
er should thus be lower in the investigated case of trans-
3j.[26,27]
As mentioned above, for meso-configured- and thus achi-
ral cis isomers derived from symmetric dienones 2 only one
of two possible cis stereoisomers is formed. Either the azlac-
tone carbonyl moiety or the N atom could, in principal, be
in the cis position to the residues R1/R2. The spirocarbon is
thus a center of pseudoasymmetry.[28] Notably, also for un-
symmetrical dienones only one of the possible two cis dia-
stereomers is formed. X-ray crystal structure analyses of cis-
3a, cis-3b, cis-3h, cis-3i, and cis-3m show that in the cis dia-
stereomers the azlactone carbonyl moiety always adopts the
axial position (Figure 6).[29]
Scheme 2. Control experiments with related monopalladacycle catalysts.
monopalladacycles 5 and 6 (Scheme 2), which are structural-
[30]
À
ly related to [FBIP Cl]2. Monopalladacycles 5 and 6 both
provided the spirocyclic product trans-3a in significant
amounts, with a higher activity and good enantioselectivity
for the sterically less-encumbered palladacycle 5.
These results indicate that a bimetallic intramolecular
mechanism is not essential in the double 1,4-addition ap-
proach using dienone substrates 2. The energetically lower
LUMOs of the dienones with their extended cross-conjugat-
ed p-systems might more readily allow for a monometallic
pathway, in which the dienone is not activated by a PdII
center.
The higher electrophilicity of the divinylketones has been
confirmed by quantum mechanical computations. By using
the DFT/B3LYP/6-31G* method, the LUMOs of dibenzyli-
dene acetone (2a) and chalcone were compared. In a
vacuum, the LUMO of 2a was found to be 14.7 kJmolÀ1
lower in energy than the LUMO of chalcone. In acetic acid
the energy difference was calculated to be 16.3 kJmolÀ1,
again with a lower LUMO energy for 2a.
Both trans diastereomers of the spirocyclic products 3 are
generated with high enantioselectivity in most cases. Nota-
bly, compared to the major products obtained from simple
enones,[13] the configuration is inverted at the b-positions to
the keto group hence preferring the S configuration. The
facial differentiation of the Michael acceptor moieties is
thus different for enones and dienones. In our previous stud-
ies with enones, we have explained the preference for the R
configuration at the b-position to the keto group of product
(R,R)-8 by coordination of the carbonyl moiety of the enone
in the assumed catalytic intermediate 7 (Scheme 3), whereas
the S configuration in the b-position to the keto group of
product (R,S)-8 would have been expected by face-selective
olefin coordination in 9.[13c]
Figure 6. X-ray crystal structure analyses of the cis-configured spirocyclic
azlactones cis-3a (top left), cis-3b (top right), cis-3h (middle left), cis-3i
(middle right), and cis-3m (bottom) to determine the relative configura-
tion.
Mechanistic considerations: In the 1,4-addition of 2-Ph-sub-
stituted azlactones to give simple enones we have previously
found that a bimetallic mechanism is likely to be preferred,
because significantly lower product yields were obtained
with related monopalladacycles.[13] Moreover, the product
was formed with only low-to-moderate enantioselectivity
with monopalladacycles. We have explained the preference
for a bimetallic catalyst by a simultaneous activation of the
enone substrate and the azlactone through a bimetallic coor-
dination mode.[13c,d] To clarify if an intramolecular bimetallic
activation mode is also likely in the title reaction with di-
vinylketones, control experiments have been performed with
As discussed above, the higher electrophilicity of dienones
most likely also allows for a rapid monometallic reaction
pathway, in which the dienone is not further activated by a
PdII center. In this mechanism, only the azlactone would be
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Catalytic Asymmetric Synthesis
FULL PAPER
azlactone to simple enones,[13c] this reaction provided two
almost racemic regioisomeric 1,4-addition products 11 and
12 (ratio of 2:1). Due to this observation it is likely that the
initial intermolecular Michael additions of the glycine-de-
rived azlactone 1 to dienones 2 also proceed with moderate
enantio- and regioselectivity.
The observation that the FBIP catalyst is not capable of
setting up the configuration of the spirocenters of trans-3
with a high level of stereocontrol, might be the result of this
low regioselectivity for the initial 1,4-addition step.[31] The
configuration of the spirocenters is defined in the subse-
quent intramolecular 1,4-addition step (Scheme 5).[32] At
least two scenarios are possible for each of the initial regioi-
someric 1,4-addition products 13 and 14: the enone double
Scheme 3. Top: Possible dual-activation mode to rationalize 1) the reac-
tivity of FBIP in the 1,4-addition of 2-Ph-azlactones and enones and
2) the absolute and relative configuration of the reaction products (R,R)-
8. Bottom: Initially assumed bimetallic activation mode, in which the
enone is activated by face-selective coordination of the C=C double bond
in 9 (minimizing repulsive interactions between the ferrocene core and
the enone residues). This mechanism would provide an S configuration at
the b-position to the carbonyl moiety, which is not observed.[13c]
activated as nucleophilic species in the intermolecular Mi-
chael-addition step by coordination to a PdII center. Com-
pared with the bimetallic mechanism with enones, this
single-point activation might result in a lower facial differen-
tiation with the dienone substrates in the initial 1,4-addition
step, because the latter substrate would not be pre-organ-
ized by interaction with the catalyst. A moderate stereose-
lectivity would be the stereochemical consequence.
Unfortunately, despite considerable efforts we were not
able to isolate or detect the initial 1,4-addition monoadducts
to determine the enantioselectivity of the initial Michael-ad-
dition step. Evidently, the intramolecular 1,4-addition pro-
ceeds much faster than the intermolecular one. As a model
reaction, we have therefore investigated the 1,4-addition of
the azlactone, which is formed in situ from racemic N-ben-
zoyl alanine 10, to the unsymmetrical enone 2j (Scheme 4).
In contrast to the enantioselective addition of the same
Scheme 5. Possible explanation for the formation of two trans dia
ACHTUNGTRENNUNGstereo-
AHCTUNGERTGmNNUN ers and the generation of the S configuration at the former enone b-
Scheme 4. Model reaction of the intermolecular 1,4-addition with dien-
ones.
carbon atom in the cyclization step. Only the S-configured initial 1,4-ad-
dition products 13 and 14 are shown for simplicity.
Chem. Eur. J. 2013, 19, 8342 – 8351
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8347

R. Peters et al.
bond could, for example, be activated in a face-selective
manner by coordination to a PdII center. An S configuration
for the emerging stereocenter at the former enone b carbon
atom would be expected in that case, because 1) repulsive
interactions between the catalyst core and the coordinated
dienone are minimized in the suggested coordination
mode[33,34] and 2) the azlactone enolate is expected to attack
from the outer-sphere (see transition states 15 and 17). Al-
ternatively, the azlactone N atom could coordinate to a Pd
center to facilitate the enolate formation triggering the sub-
sequent cyclization step (see transition states 16 and 18). Ir-
respective of which of these two activation pathways might
be preferred, the ratio of the trans diastereomers would be
predetermined by the regioselectivity of the initial intramo-
lecular 1,4-addition step.
ical interest.[38] They often restrict the conformational flexi-
bility of peptides and induce a unique peptide folding,
whereas at the same time the hydrophobicity and stability
against peptide degradation are noticeably increased.[38,39]
The spirocyclic azlactones trans-3 were therefore studied for
the formation of protected constrained cyclohexane ana-
logues 19 of phenylalanine (Table 3).[40] These compounds
Table 3. Synthesis of constrained cyclohexane analogues 19 of phenylala-
nine through nucleophilic azlactone ring-opening with methanol.
The coordination of acetonitrile in the activated catalyst
À
FBIP X (Figure 1) should be trans to the N donor, in agree-
Entry
3
19
R1
R2
19
ment with the solution structure of FBIP catalysts carrying
an aromatic sulfonate counterion.[15d] In addition, there
seems to be a general preference in ferrocene-based pallada-
cycles for coordination of neutral ligands trans to the N
[%][a]
1
2
3
4
5
6
7
a
b
c
g
h
i
a
b
c
g
h
i
Ph
Ph
90
86
100
80
81
83
4-MeO-C6H4
4-Me-C6H4
Ph
Ph
Ph
Ph
4-MeO-C6H4
4-Me-C6H4
4-MeO-C6H4
4-Me-C6H4
4-Br-C6H4
2-furyl
donors and of anionic ligands trans to the
C do-
nors.[16c,30e,35,36] We thus assume that substitution of acetoni-
trile by the substrate molecules should take place at the po-
sition trans to the N donors leading to the reaction pathways
depicted in Scheme 5,[37] but a substrate coordination cis to
the N donors cannot be completely excluded.
m
m
93
[a] Yield of the isolated product.
As mentioned above, the cis diastereomers of 3 are nearly
racemic using unsymmetrical dienones. The amount of cis-3
is considerably increased in the presence of stoichiometric
or excess amounts of NaOAc (see Table 1). On the other
hand, in the absence of catalyst, almost no cis product is
formed and the trans isomer is the major product (Table 1,
entry 7). It is thus likely that the catalyst is also involved in
the formation of the cis-configured side product. Only one
of two possible cis isomers has been detected in nearly all
cases.[20] Notably, the cis isomer that has been formed should
be the thermodynamically less-favorable one, as the azlac-
tone carbonyl group (and not the sterically less-demanding
N atom) adopts the axial position thereby resulting in stron-
ger 1,3-diaxial interactions in the chairlike conformers
(Figure 6). This has been confirmed by DFT calculations
(B3LYP/6-31G* method), which suggest that the observed
isomer is by about 3.7 kJmolÀ1 higher in energy than the al-
ternative isomer.
are of interest as building blocks for the synthesis of artifi-
cial peptide analogues with controlled folds in the peptide
backbone, since they are able to restrict the c1 torsion
angle.[41] Moreover they are important in peptide receptor
recognition processes.[41] Treatment of trans-3a with MeOH
and TMSCl at ambient temperature gave access to diaster-
eomerically pure methyl ester 19a in high yield and with an
unchanged ee value of 95% (Table 3, entry 1).
Compound 19a was also obtained from the major diaster-
eomer of trans-3j (for which the absolute configuration has
been determined by X-ray crystal structure analysis (see
Figure 2, top, major enantiomer)) by reductive removal of
the Cl atom in MeOH (Scheme 6). Trans-3j and trans-3a
have formed the same enantiomer of 19a, thus confirming
the S,S configuration for trans-3a.
Formation of the cis-configured side product should thus
be kinetically controlled. It might be that the R-configured
monoadducts (R)-13 and (R)-14 mainly react to cis-3, that is,
6R,10S/6S,10R-configured products, as a result of the above
described preference of the catalyst for the generation of
the S-configured stereocenters at the b-position to the keto
moiety in the cyclization step. Nearly racemic products
would again be the consequence of a low regioselectivity in
the initial intermolecular 1,4-addition step.
Azlactone derivatization: a,a-Disubstituted a-amino acids
(quaternary amino acids) are of biological and pharmacolog-
Scheme 6. Reductive removal of the Cl substituent in trans-3j plus azlac-
tone ring opening to confirm the absolute configuration of trans-3a.
8348
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Chem. Eur. J. 2013, 19, 8342 – 8351

Catalytic Asymmetric Synthesis
FULL PAPER
Methanolysis of several other spirocyclic azlactones pro-
ceeded with similar efficiency (Table 3). In entries 4–7 the
diastereomeric ratios of the two trans isomers were identical
in the starting material and the corresponding product. If
the reaction mixture was buffered by using iPr2NEt, the
azlactone ring-opening by MeOH was decelerated and di-
methylketal 20 was formed. The X-ray crystal structure
analysis of this compound again confirmed the S,S configu-
ration of trans-3a (Scheme 7).[42] Also, in this case a twist
conformer was found in the solid state.
trophilicity of dienones presumably allows for a monometal-
lic reaction pathway, in which the catalyst only activates the
pronucleophile for the initial, slower intermolecular 1,4-ad-
dition. Depending on the substitution pattern of the dien-
ones, the trans isomers can prefer a twist- rather than a
chair conformer, both in the solid state and in solution, to
minimize 1,3-diaxial interactions. Only one cis diastereomer,
which is either achiral or nearly racemic, has been detected
as a side product. We have shown that the spirocyclic reac-
tion products can, for example, serve as precursors for the
formation of cyclic quaternary amino acids by azlactone ring
opening.
Experimental Section
À
General procedure for the activation of precatalyst [FBIP Cl]2: The pre-
À
catalyst [FBIP Cl]2 (1 equiv) and silver triflate (4 equiv) were dissolved
À
in acetonitrile (1 mL per 5 mg [FBIP Cl]2) and stirred at room tempera-
ture overnight. Afterwards, the mixture was filtered through Celite and
free acetonitrile was removed under reduced pressure (ca. 5 min at
15 mbar and RT). A stock solution of the activated catalyst in a mixture
of acetic acid and acetic anhydride (70:30) was subsequently prepared
(typically 1 mmol precatalyst per 150 mL solvent).
General procedure for the catalytic asymmetric synthesis of spirocyclic
azlactones: N-Benzoyl glycine (1 equiv, 0.60 mmol, 108 mg), sodium ace-
tate (2 equiv, 1.20 mmol, 98.4 mg), and the corresponding dienone (1 or
2 equiv, 0.60 or 1.20 mmol) were charged to a vial. The activated catalyst
À
(prepared from [FBIP Cl]2 (0.02 equiv, 12.0 mmol, 29.2 mg) and silver tri-
flate (0.08 equiv, 48.0 mmol, 12.3 mg) as described in the general proce-
dure) was added as a stock solution (1.80 mL, AcOH/Ac2O, 70:30). The
resulting mixture was warmed to 308C for 24 h or to 558C for 20 h. After
cooling to room temperature, the mixture was taken up in CH2Cl2 (ca.
40 mL) and was washed with sat. aq. NaHCO3 and was then dried over
Na2SO4. The targeted product was isolated by using silica gel chromatog-
raphy. Nearly racemic reference samples were synthesized in the same
manner by use of approximately a 1:1 mixture of both catalyst enantiom-
ers on a 50 mmol scale.
Scheme 7. Synthesis and X-ray crystal structure analysis of dimethylketal
20.
Conclusion
General procedure for the azlactone ring-opening esterification: A mix-
ture of the corresponding spirocyclic azlactone
3 (1 equiv), TMSCl
(4 equiv), and methanol was heated to 408C for 4 h. After removal of the
volatiles, the crude product was purified by silica gel chromatography.
We have described a catalytic asymmetric tandem reaction
to prepare highly enantioenriched azlactone/cyclohexanone
spirocycles through a double Michael-addition approach (a
formal [5+1] cycloaddition) in which an achiral glycine-de-
rived azlactone pronucleophile is generated in situ from N-
benzoylated glycine and acetic anhydride. Both symmetrical
and unsymmetrical divinylketones have been investigated in
the title reaction, which generates up to three contiguous
stereocenters, one of which is quaternary. X-ray crystal
structure analyses have revealed the preferred trans configu-
ration of the cyclohexanone rings with regard to the two di-
enone substituents and the absolute configuration. Unfortu-
nately, the catalyst system is not capable of setting up the
configuration of the spirocenter with a high level of stereo-
control in the trans products and therefore two trans diaster-
eomers are formed in similar quantities by using unsymmet-
rical dienones. Nevertheless, both trans diastereomers are
formed with high enantioselectivity in most cases. Control
experiments with related monopalladacycles suggest that a
bimetallic mechanism is not necessarily required for enan-
tioselective product formation. The comparatively high elec-
Acknowledgements
This work was financially supported by the Deutsche Forschungsgemein-
schaft (DFG, PE 818/4–1).
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Chem. Eur. J. 2013, 19, 8342 – 8351
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www.chemeurj.org
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run (see the Supporting Information).
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[21] CCDC-918517 (trans-3j, major diastereomer and enantiomer),
CCDC-918519 (trans-3a), CCDC-918526 (trans-3d), CCDC-918518
(trans-3l, major diastereomer), and CCDC-918524 (trans-3e) con-
tain the supplementary crystallographic data for this paper. These
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Catalytic Asymmetric Synthesis
FULL PAPER
data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[22] The absolute configuration previously tentatively assigned to trans-
3a in ref. [2] is not correct. The authors wish to apologize for any in-
convenience caused by the initial misassignment.
[23] CCDC 918527 (trans-3l, minor diastereomer) contains the supple-
mentary crystallographic data. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
the usual reaction conditions does not form any R,S-configured
isomer and trans-3a was reisolated in quantitative yield with an un-
changed ee value of 95%. Based on the slow retro-Michael reaction
of the initial 1,4-addition product in combination with the very rapid
and irreversible intramolecular Michael addition, a dynamic kinetic
resolution is unlikely to have a large impact in the present case.
[32] Alternatively, the facial selectivity of the azlactone-enolate faces
might be low in transition states similar to 15–18, but lacking the
suggested chelation by Na+.
[24] M. Karplus, J. Am. Chem. Soc. 1963, 85, 2870.
[33] Note that in square-planar PdII complexes, the olefin axis is usually
perpendicular to the olefin square plane. See: P. M. Henry, Hand-
book of Organopalladium Chemistry for Organic Synthesis Vol. 2,
Wiley-Interscience, New York, 2002, p. 2119 and cited references.
[34] By coordination of the alternative olefin face either the olefin sub-
stituent R1/R2 or the carbonyl moiety plus the neighboring a-CH2
would point to the ferrocene bulk of the catalyst thus resulting in
stronger repulsive interactions.
[25] D. J. Nelson, N. C. Bramer, J. Chem. Educ. 2011, 88, 292.
[26] Preferences for a twist conformer have also been reported for other
1,3-trans-disubstituted six-membered rings: a) H. Kessler, V. Gusow-
ski, M. Hanack, Tetrahedron Lett. 1968, 9, 4665; b) N. L. Allinger,
J. A. Hirsch, M. A. Miller, I. J. Tyminski, F. A. Van-Catledge, J. Am.
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Org. Chem. 2005, 70, 10726.
[27] Compound trans-3a, which was crystallized at 38C, shows a twist
conformation in the solid state. In contrast, for example, trans-3d,
trans-3e, and trans-3l, which were crystallized at room temperature,
show a chair conformation. This might be a consequence of the
shifted equilibrium at different temperatures, but might also be ex-
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To investigate if dynamic kinetic resolution might also play a role in
our study, we have examined if the formation of 11 and 12 is reversi-
ble. The isolated compounds 11 and 12 were thus treated with the
usual reaction conditions of the catalysis. Regioisomeric mixtures
have indeed been obtained by using the single regioisomers. Howev-
er, the equilibration is rather slow (see the Supporting Information).
In contrast, the formation of the S,S-configured spirocyclic product
trans-3a was found to be irreversible (see the Supporting Informa-
tion). Treating the isolated diastereomerically pure material under
Received: January 21, 2013
Published online: April 23, 2013
Chem. Eur. J. 2013, 19, 8342 – 8351
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8351