Catalytic asymmetric synthesis of functionalized α,α- disubstituted α-amino acid derivatives from racemic unprotected α-amino acids via in-situ generated azlactones

Article abstract of DOI:10.1002/adsc.201200085

Masked and activated highly enantioenriched α,α-disubstituted α-amino acids with an additional adjacent stereocenter were formed by a tandem reaction involving five steps using racemic unprotected amino acid substrates. Key step is the 1,4-addition of in-situ generated azlactones to a broad number of enones. The products of this step-economic route can, e.g., be useful for a divergent and rapid access to biologically interesting unnatural glutamic acid derivatives. Copyright

Full text of DOI:10.1002/adsc.201200085

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DOI: 10.1002/adsc.201200085
Catalytic Asymmetric Synthesis of Functionalized
a,a-Disubstituted a-Amino Acid Derivatives from Racemic
Unprotected a-Amino Acids via in-situ Generated Azlactones
Manuel Weber,a Wolfgang Frey,a and Renꢀ Petersa,*
a
Institut fꢁr Organische Chemie, Universitꢂt Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
Fax : (+49)-(0)711-685-54330; e-mail: rene.peters@oc.uni-stuttgart.de
Received: December 24, 2012; Revised: March 2, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200085.
Abstract: Masked and activated highly enantioen-
riched a,a-disubstituted a-amino acids with an ad-
ditional adjacent stereocenter were formed by
a tandem reaction involving five steps using racemic
unprotected amino acid substrates. Key step is the
1,4-addition of in-situ generated azlactones to
a broad number of enones. The products of this
step-economic route can, e.g., be useful for a diver-
gent and rapid access to biologically interesting un-
natural glutamic acid derivatives.
thesis of a,a-disubstituted a-amino acids owing to the
presence of orthogonal nucleophilic and electrophilic
reactive sites in the heterocyclic systems.[3]
Recently, we have reported the first catalytic asym-
metric 1,4-addition of azlactones to enones.[6e] In that
study we observed that under the reported reaction
conditions the azlactone formed an equilibrium with
a mixed anhydride by azlactone ring opening/closing
with the solvent acetic acid. Herein, we describe
a one-pot procedure for the catalytic asymmetric con-
struction of functionalized amino acid derivatives 3
from inexpensive unprotected racemic a-amino acids
1 (Scheme 1). The tandem sequence[9] involves both
an N- and O-amino acid acylation, a cyclization to
form racemic azlactones 5, an enolization to 5’ and
the catalytic asymmetric addition to the Michael ac-
ceptor.[10] Product formation is catalyzed by the readi-
ly accessible planar chiral ferrocene bispalladacycle
Keywords: azlactones; bimetallic catalysis; domino
process; dynamic kinetic resolution; glutamic acid
derivatives
Scalemic a,a-disubstituted a-amino acids are current-
ACHTUNGTRNE[NUNG FBIP-Cl]2 (4 steps from ferrocene) after activation
ly receiving large interest for a number of reasons.[1] with a silver salt.[11,12] This catalyst has recently
A large part of the high motivation to intensively emerged as a powerful p-acid to stereospecifically ac-
study a,a-disubstituted a-amino acids is based on tivate olefins[13] and to promote bimetallic reaction
their ability to restrict the conformational flexibility pathways by intramolecular cooperation of the two
of peptides and to induce a unique peptide folding, Pd centers.[6e,14,15]
while at the same time hydrophobicity and stability
Attempts to utilize the reaction conditions of our
previous study (i.e., 2 mol% [FBIP-Cl]2, 8 mol%
against peptide degradation are increased.[1,2]
AHCTUNGTRENNUNG
Azlactones 5 [systematic name: oxazol-5-(4H)- AgOTf, 10 mol% NaOAc in AcOH/Ac2O at room
ones] are masked and activated amino acid deriva- temperature) in the model reaction of racemic unpro-
tives that have recently been employed for the cata- tected norvaline (1A) with enone 2a gave the desired
lytic asymmetric construction of a,a-disubstituted a- tandem reaction product with an excellent enantio-
amino acids taking advantage of the pronounced ten- meric excess (ee) of 96% (Table 1, entry 1), yet in
dency of the heterocycles to enolize (pKa = Æ9) due poor yield mainly due to a low conversion. Since
to the aromatic character of the enol tautomer 5’ (see
ACHTUNGTRNE[NGNU FBIP-Cl]2 itself shows almost no catalytic activity as
Scheme 1).[3] The nucleophilic azlactone C-4 position a result of the relatively strongly coordinating chlo-
could, e.g., be employed for catalytic asymmetric sub- ride counterions,[13b] it was activated with AgOTf
stitutions,[4] additions,[5,6] and rearrangements[7] to leading to a counterion exchange with precipitation of
form tetrasubstituted stereocenters[8] with a high level AgCl which is removed by filtration. The model reac-
of enantioselectivity. The use of azlactones 5, which tion was then conducted at temperatures up to 708C,
are usually accessible in 2–4 steps from amino acids, but the product was still formed in low yield, mainly
is particularly attractive for the diversity oriented syn- because of the competing formation of the regioiso-
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Scheme 1. One-pot tandem reaction sequence to form the masked and activated a,a-disubstituted a-amino acid derivatves 3
bearing an additional stereocenter in the b-position.
Table 1. Elaboration of the reaction conditions with norvaline (1A) and enone 2a.[a]
#
R
X
Y
Solvent
T [8C] t [h] 3-R-Aa/6-R-Aa Yield [%][b] Yield [%][b] dr
ee [%][c]
6-R-Aa
3-R-Aa
3-R-Aa[b] 3-R-Aa
1
2
3
4
5
6
7
Me
Me
Me
Et
i-Bu
t-Bu
H[d]
Ph
2
2
3
3
3
3
3
3
3
3
3
10
10
25
25
25
25
25
25
25
–
–
–
–
–
–
–
–
–
23
50
70
70
70
70
70
70
70
30
18
5
5
5
5
5
5
5
2.7:1
1.7:1
2.0:1
2.4:1
4.3:1
n.d.
6
27
22
20
17
45
43
48
43
<4
<2
69
62
73
52
>98:2
>98:2
>98:2
>98:2
>98:2
n.d.
96
97
95
95
72
n.d.
–
90
66
92
75
10
<4
<2
<2
<2
<2
<2
n.d.
–
8
>34:1
>31:1
>36:1
>26:1
>98:2
>98:2
>98:2
>98:2
9[e]
10
Ph
Ph
25 THF/PhMe 10:1 70
25 THF 70
5
5
11[e] Ph
[a]
Reactions were performed in a parallel synthesizer heated by a metal block.
Determined by H NMR of the crude product using mesitylene as internal standard (n.d.: not determined).
Determined by HPLC.
A mixture of formic acid and acetic anhydride was used.
No benzoic acid was added.
[b]
[c]
[d]
[e]
1
1
meric C-2 addition product 6-Me-Aa (entries 2 and 3)
A kinetic investigation at 708C by H NMR then
which is generated as a diastereomeric mixture, revealed that N-acetylnorvaline and azlactone 5-Me-
whereas the targeted regioisomer 3-Me-Aa is nearly A are rapidly formed in comparable amounts, which
diastereomerically pure.
gradually decrease due to the formation of both Mi-
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Catalytic Asymmetric Synthesis of Functionalized a,a-Disubstituted a-Amino Acid Derivatives
Figure 1. Kinetic control of the model reaction (Table 1, entry 3).
chael addition regiosiomers. The latter are initially tion pathway, the coordination of one dehydroproline
formed with similar rates (Figure 1), but the ratio 3- would already be deleterious for the catalyst activity.
Me-Aa/6-Me-Aa steadily increases due to decomposi-
tion of 6-Me-Aa.
Various combinations of carboxylic acids and anhy-
drides (RC=O)2O were then surveyed in order to de-
Attempts to isolate the catalyst after the reaction crease the nucleophilicity of C-2, thus minimizing the
led to the identification of a second side product obvi-
ously inhibiting the catalyst by the formation of the
C2-symmetrical complex 7 which was identified by an
X-ray crystal structure analysis (Figure 2).[16] Complex
7 is the almost exclusively found bispalladium species
at the end of the reaction in acetic acid/acetic anhy-
dride. The inhibiting side product, a dehydroproline
derivative with a tetrasubstituted carbon at C-2 and
two additional stereocenters at C-3 and C-4, chelates
each Pd-center of the bimetallic catalyst. The 3,4-di-
hydropyrrole might either be formed via a 1,3-dipolar
cycloaddition pathway,[17] or alternatively by the unde-
sired Michael addition at C-2 of the azlactone fol-
lowed by an intramolecular Mannich addition, initial-
ly generating the bicyclic proline intermediate 8
(Scheme 2). The latter could subsequently undergo
a ring opening of the N,O-acetal moiety giving 7.
The fact that both Pd centers of the FBIP system
bind almost exclusively to a dehydroproline molecule
demonstrates that the corresponding binding con-
stants are arguably much higher than those of the tar-
geted product 3-Me-Aa, most likely due to the pres-
ence of the carboxylate moiety as anionic donor,
whereas 3-Me-Aa contains only neutral donors. The
anionic donor in 7 (i.e., the carboxylate group) binds
cis, and the neutral donor (i.e., the imino group)
binds trans to the imidazoline moiety as a result of
Figure 2. X-ray crystal structure analysis of the C2-symmetric
a trans-effect,[18] in agreement with our previous find-
complex 7, which is formed during the catalysis event in
ings for ferrocene imidazoline palladacycles.[13b,19] If
AcOH/Ac2O. H atoms are omitted and only one half of the
the formation of 3-Me-Aa follows a bimetallic reac- C2-symmetrical 7 is shown for clarity.
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more.[21] The targeted product 3-Ph-Aa was formed in
considerably better yield despite a heterogeneous re-
action mixture in that case (entry 8). Addition of vari-
ous co-solvents gave homogeneous mixtures and thus
allowed for a better reproducibility, while there was
almost no impact on the stereoselectivity.[22] The best
data were obtained with a mixture of THF/toluene
(10:1, entry 10).[23] The presence of benzoic acid is es-
sential for high enantioselectivity as the experiments
in entries 9 and 11 reveal, in which the reaction was
performed without addition of benzoic acid. In that
case formation of Pd black was observed.[24]
Scheme 2. Mechanistic proposal for the formation of the in-
hibited catalyst 7.
formation of the undesired regioisomer 6 and the 1,3-
With the optimized reaction conditions from the in-
dipolar cycloaddition product blocking the catalyst.[20] itial screening, which was performed in a parallel syn-
More bulky alkyl groups R resulted, in general, in thesizer, preparative experiments were conducted for
a lower reactivity (Table 1, entries 4–6), but unfortu- various enones and unprotected racemic amino acids
nately not only at C-2. For R=H (formic acid, (ethylglycine, norvaline, norleucine, leucine, phenyl-
entry 7), no product was formed as a consequence of
ACHTUNGTRENaNGNU lanine, glutamic acid 5-methyl ester) using a conven-
catalyst decomposition (formation of Pd black). In tional reaction set-up (Table 2). As a general trend
contrast, R=Ph (benzoic acid/anhydride) sheparded the amino acid reactivity towards reaction with the
the reactivity to the C-4-position and the undesired same enone increased with decreasing steric bulk of
Michael addition regioisomer was not detected any- the amino acid side chain R1 (compare entries 1, 3,
Table 2. Application of the optimized reaction conditions to different unprotected racemic amino acids and Michael accept-
ors.[a]
#
3-Ph
R1
R2
R3
Yield[b] [%]
ee [%][c]
1
2
3
4
5
6
7
8
3-Ph-Ba
3-Ph-Bb
3-Ph-Aa
3-Ph-Ac
3-Ph-Ad
3-Ph-Ae
3-Ph-Af
3-Ph-Ag
3-Ph-Ah
3-Ph-Ai
3-Ph-Aj
3-Ph-Ca
3-Ph-Cb
3-Ph-Cd
3-Ph-Ce
3-Ph-Ck
3-Ph-Da
3-Ph-Ea
3-Ph-Fa
3-Ph-Fl
Et
Et
Ph
4-Br-C6H4
Ph
4-MeO-C6H4
4-Cl-C6H4
2-Cl-C6H4
4-O2N-C6H4
2-furyl
i-Pr
Ph
Ph
Ph
4-Br-C6H4
4-Cl-C6H4
2-Cl-C6H4
n-Pr
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
iPr
90
90
87
75
73
76
58
76
62
49
41
72
71
72
72
77
52
66
73
65
78
71
90
82
84
85
80
82
81
91
78
96
88
87
90
90
73
74
87
75
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
i-Bu
Bn
9
10
11[d]
12
13
14
15
16
17[e]
18[d]
19
20
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
T
A
Ph
3,4-(MeO)2C6H3
[a]
Reactions were performed in Schlenk tubes heated by an oil bath.
Yield of isolated product.
Determined by HPLC.
[b]
[c]
[d]
[e]
10 mol%
ACHTUNGTRENNUNG
7.5 mol% ACHTUNGTRENNUNG
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Catalytic Asymmetric Synthesis of Functionalized a,a-Disubstituted a-Amino Acid Derivatives
12, 17–19) and the best yields were thus found for
sterically less demanding unbranched alkyl substitu-
ents R1 allowing for product formation in up to 90%
yield for the one-pot, five-step procedure (average
yield per step in entry 1: 98%), whereas the b-
branched isobutyl residue R1 [leucine (1D), entry 17]
or a benzyl group [phenylalanine (1E), entry 18] led
to product formation in moderate yields (52% and
66%, respectively; average yield per step 88% and
92%).
The reported methodology is also useful for a rapid
access to unnatural glutamic acid derivatives. Natural
glutamic acid acts as an essential neurotransmitter in
the mammalian central nervous system and is playing
a key role in the pathogenesis of neuronal damage
that causes various neuronal diseases by interaction
Scheme 3. Investigation of structurally related ferrocene
mono-palladacycle catalysts for comparison to [FBIP-Cl]2
(Table 2, entry 3, ee 3-Ph-Aa: 90%, yield 3-Ph-Aa: 87%).
with glutamate membrane receptors.[25] Investigation
of unnatural glutamic acid derivatives is considered to
be a useful tool to study the role of these receptors as
well as their modulation mechanism in the central
AHCTUNGTRENNUNG
nervous system.[26] An operationally simple and rapid both metal centers in the 1,4-addition event using
catalytic asymmetric access might contribute to accel- FBIP.
erate the progress in this field. Entries 19 and 20 in
Due to the synthetic versatility of the functional
Table 2 demonstrate that a-alkylglutamic acid deriva- groups present in the tandem reaction products 3,
tives are accesible in diastereomerically pure form a rich follow-up chemistry can be envisaged. This is
from racemic glutamic acid 5-methyl ester (1F) in showcased by two complementary routes to the above
good yields and with good to high enantioselectivity.
mentioned class of a-alkylglutamic acid derivatives
Moreover, a broad variety of enones with R2/R3 = (Scheme 4). Nucleophilic ring opening of 3-Ph-Fa
(het)aryl/alkyl (entries 1–8, 10, 12–15, 17–20), alkyl/ with NaOH gave access to the a-alkyl N-benzoylglu-
alkyl (entries 9 and 16) or aryl/aryl (entry 11) is ac- tamic acid 14, whereas MeOH/TMSCl provided the
comodated under the reaction conditions, albeit reac- corresponding dimethyl ester 15. Compounds 14 and
tivity and diastereoselectivity are lower in the latter 15 are thus accessible from racemic glutamic acid 5-
case. Remarkably, for alkyl/alkyl combinations, an i- methyl ester in just two steps in 54% and 58% overall
Pr moiety as R2 is also well tolerated (entry 9) despite yields, respectively. Alternatively, regioselective
the presence of three vicinal branched sp3-C atoms in Baeyer–Villiger oxidation of the i-Pr-ketone moiety
3-Ph-Ah. Investigation of various functional groups in 3-Ph-Ai after nucleophilic ring opening with
on aryl moieties R2 confirmed that electronic and MeOH/TMSCl provided the a-alkylglutamic acid de-
steric effects play only a minor role with regard to the rivative 12. By means of asymmetric catalysis 2,3-di-
enone. Substrates equipped with a strong p-donor
substituent such as p-OMe (entries 4 and 20), p-ac-
ceptor substituents such as p-NO2 (entry 7), s-accept-
or substituents such as o-Cl (entries 6 and 15) or p-Cl
(entries 5 and 14) or substrates bearing electron-rich
heterocycles like 2-furyl (entry 8) gave useful results
in terms of yield and enantioselectivity. Aryl bromides
can be used in the presence of the Pd catalyst (en-
tries 2 and 13), since FBIP is relatively inert against
formation of Pd(0) by catalyst decomposition under
the acidic reaction conditions.
Structurally related ferrocene monopalladacycles
performed significantly less enantioselective than
FBIP (Scheme 3). Moderate enantioselectivity was,
for instance, attained in the model reaction of 1A and
2a with precatalyst 9[19b,c] whereas the sterically more
demanding pentaphenylferrocene derivatives 10[19b,c,27]
and 11[19c] resulted in low yields and nearly racemic
Scheme 4. Synthesis of unnatural a-alkyl (pyro)glutamic
product. These data might point to a cooperation of acid derivatives 12–15.
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ACHTUNGTRENNUNGsubstituted glutamic acid derivatives were previously General Procedure for the Catalytic Asymmetric
only accessible in single cases, using the 1,4-addition Synthesis of a,a-Disubstituted Amino Acid
of isolated azlactones to acylphosphonates due to the Derivatives
C-2/C-4 regioselectivity issue. In addition, these prod-
The corresponding racemic amino acid (1, 1.00 equiv.,
0.20 mmol), the corresponding enone (2, 6.00 equiv.,
1.20 mmol), NaOAc (0.25 equiv., 50.0 mmol, 4.10 mg), ben-
ucts were only accessible with moderate enantiomeric
excess (up to 55% ee).[6c]
Compound 12 was also shown to serve as a direct
precursor to the N-unprotected pyroglutamic acid de-
rivative 13 with adjacent tetra- and trisubstituted ste-
reocenters. Treatment of 12 with Cs2CO3 in MeOH
provided the scalemic heterocycle in high yield.
zoic acid (35 equiv., 7.00 mmol, 855 mg) and benzoic anhy-
dride (20 equiv., 4.00 mmol, 905 mg) were successively
charged into a flask. To this mixture was added the activated
catalyst (see above) as a stem solution in THF/PhMe
(0.03 equiv., 6.00 mmol, prepared from 14.6 mg ACTHNURGTNEUNG[FBIP-Cl]2
in 440 mL THF/PhMe 10/1). The resulting slurry was heated
to 708C under vigorous stirring for 7 h. After this time, the
mixture was cooled to room temperature. The solidified
crude product was taken up in dichloromethane (ca. 20 mL)
and was washed once with saturated aqueous NaHCO3. The
organic layer was separated, then dried over Na2SO4, fil-
tered and concentrated. The targeted amino acid derivative
was purified by silica gel column chromatography. To com-
pletely remove benzoic anhydride, the fractions containing
the target product were concentrated and subjected to an-
other silica gel column. Remaining benzoic acid was re-
moved by washing the fractions containing the target prod-
uct with saturated aqueous NaHCO3 solution, then Na2SO4
was used for drying.
In conclusion, we have developed a tandem process
that is able to directly transform unprotected racemic
amino acids by a single operation into masked and ac-
tivated scalemic a,a-disubstituted a-amino acids. The
tandem sequence involves an N- and O-amino acid
acylation, a cyclization to form racemic azlactones, an
enolization and the asymmetric addition to the enone.
Key for a high efficiency is the choice of the carboxyl-
ic anhydride required for the in-situ formation of the
azlactone. With aliphatic anhydrides like Ac2O the
formation of larger quantities of an undesired regioi-
someric Michael addition side product was observed,
whereas with benzoic anhydride addition of the azlac-
tone C-4 atom is almost exclusively favored. It was
also found that the bis-Pd-catalyst is inhibited by
a strongly binding dehydroproline side product which
is generated via a (formal) 1,3-dipolar cycloaddition,
also caused by the nucleophilic character of the azlac-
tone C-2 atom when acetic anhydride was used. This
dehydroproline side product is less prominent with
benzoic anhydride due to a lower reactivity of C-2.
The methodology allows for a broad variability and
thus provides rapid access to biologically interesting
unnatural a,a-disubstituted a-amino acid derivatives
in a single step from inexpensive bulk chemicals. In
particular, the possibility to divergently and rapidly
synthesize unnatural glutamic acid derivatives should
be of biological interest.
Acknowledgements
This work was financially supported by the Deutsche For-
schungsgemeinschaft (DFG) (PE 818/4-1).
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6
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[21] Nevertheless, a catalyst species binding to the formal
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68/87; glyme: 56/88; diglyme: 64/87; benzene: 53/87;
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[24] This points to the formation of a Pd-alkyl intermediate
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rather than a productive protonolysis. The latter is ac-
celerated by addition of benzoic acid. A similar effect
was observed by us in a previous study, in which a bi-
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was strongly supported by detailed kinetic investiga-
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Adv. Synth. Catal. 0000, 000, 0 – 0
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COMMUNICATIONS
8 Catalytic Asymmetric Synthesis of Functionalized a,a-
Disubstituted a-Amino Acid Derivatives from Racemic
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Azlactones
Adv. Synth. Catal. 2012, 354, 1 – 8
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