One-Pot Vinylation of Azlactones: Fast Access to Enantioenriched α-Vinyl Quaternary Amino Acids

Article abstract of DOI:10.1002/ejoc.201700353

We report a fast one-pot protocol for the direct vinylation of azlactones [oxazol-5-(4H)-ones] by using as a key step an aldol addition with 2-(phenylselenenyl)acetaldehyde followed by dehydroxyselenation. The acid hydrolysis of the oxazolone ring gave the desired fully deprotected α-vinyl quaternary α-amino acids in almost quantitative yields. An enantioselective variant of the method was also developed by using catalytic chiral bases. The use of Sharpless ligand (DHQD)₂PHAL produced the final quaternary amino acids in good overall yields (62–78 %) and with ee values up to 86 %. Scaling up the optimized protocol to gram quantities did not affect the yields and ee values. We also demonstrated that the vinyl moiety installed onto the oxazolone ring can be exploited as a handle for the attachment of aryl groups through a Heck coupling reaction.

Full text of DOI:10.1002/ejoc.201700353

A Journal of
Accepted Article
Title: One-pot vinylation of azlactones: fast access to enantioenriched
α-vinyl quaternary amino acids
Authors: Massimo Serra, Eric Bernardi, Giorgio Marrubini, and Lino
Colombo
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700353
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700353
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10.1002/ejoc.201700353
European Journal of Organic Chemistry
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One-pot vinylation of azlactones: fast access to enantioenriched
α-vinyl quaternary amino acids
Massimo Serra*, Eric Bernardi, Giorgio Marrubini, and Lino Colombo*
Abstract: We report a fast one-pot protocol for the direct vinylation
of azlactones (oxazol-5-(4H)-ones) exploiting as a key step an aldol
addition with 2-(phenylselenenyl)acetaldehyde followed by
dehydroxyselenation. The acid hydrolysis of the oxazolone ring
afforded the desired fully deprotected α-vinyl quaternary α-amino
acids in almost quantitative yields. An enantioselective variant of the
method was also developed by the use of catalytic chiral bases. The
use of Sharpless ligand (DHQD)2PHAL produced the final
quaternary amino acids in good overall yields (62–78%) and ee up
to 86%. Scale-up of the optimized protocol to gram quantities did not
affect yields and ee’s. Moreover, we demonstrated that the vinyl
moiety installed onto the oxazolone ring can be exploited as a
handle for the attachment of aryl groups through a Heck coupling
reaction.
Oxazol-5-(4H)-ones (azlactones), readily available through
cyclization-dehydration of various N-protected α-amino acids,
have been proven to be excellent substrates for the synthesis of
quaternary unsaturated α-amino acids.5 However, to the best of
our knowledge, only one example of one-pot installation of
ethynyl and/or ethenyl groups at the C-4 position of the
oxazolone ring has been reported in literature.6 In their work,
Nachtsheim and co-workers described an electrophilic
alkynylation of oxazol-5-(4H)-ones using alkynyliodonium salts
as the alkyne source. Even though the method itself is practical
and suitable for the obtainment of a large range of N-benzoyl
amino acids derivatives, its major limitation is the inability to
convert the 4-ethynyl azlactones into the corresponding
unprotected α-amino acids.
In a previous work we carried out the enantioselective synthesis
of different α-vinyl quaternary amino acids exploiting
a
stereoselective alkylation of the Seebach’s oxazolidine followed
by a Wittig methylenation of the aldehyde group resulting from
hydrolysis of the oxazolidine and subsequent oxidation of the
primary alcohol.7 Since this enantioselective sequence requires
six steps (starting from Seebach’s oxazolidine), we were in need
of a more rapid synthetic protocol for the preparation of the
aforementioned derivatives. In addition, this protocol should be
amenable to be performed in an enantioselective fashion. In this
communication we report a fast access to unprotected α-alkyl, α-
vinyl α-amino acids, via one-pot vinylation of the corresponding
oxazol-5-(4H)-ones (Scheme 1). Among the various methods
able to introduce a vinyl moiety into the α-carbon of carbonyl
compounds en route to quaternary amino acids,4b, 8 we opted for
the protocol involving the reaction of an enolate with
phenylseleno acetaldehyde followed by elimination of the
phenylselenyl and hydroxyl group after the conversion of the
latter function into a better leaving group such as a mesylate.9, 10
Introduction
The synthesis of non-proteinogenic amino acids and their
incorporation into peptides or proteins for the obtainment of
chemically- and enzymatically-stable derivatives is an area of
growing interest in medicinal chemistry and biology.1 In
particular, α,α-disubstituted (quaternary) α-amino acids, due to
the lack of hydrogen at the α-position, are characterized by
restricted conformational flexibility, increased lipophilicity, and
stability towards racemization.2 Quaternary amino acids are
present in nature either in their free form or as constituents of
many biologically active natural and unnatural compounds.3
Among the various Cα-tetrasubstituted amino acids, α-vinyl
amino acids showed irreversible inhibitory effects on a variety of
PLP-dependent
enzymes,
particularly
amino
acid
decarboxylases.4 Furthermore, the straightforward conversion of
the C-C double bond into a variety of different functional groups,
including the impressive applications in C-C bond formation
afforded by olefin metathesis and Pd–catalyzed coupling
reactions, has aroused new interest in the synthesis of α-vinyl α-
amino acids as versatile building blocks for the achievement of
conformationally constrained or easily functionalizable
peptidomimetics.
Previous work:
H
O
H
O
CO2Me
R
CO2Me
N
O
N
O
CO2H
(Ref. 7)
stereoselective
alkylation
R
NHCbz
ee >94%
yields >43%
5 steps
This work:
O
OH
O
O
[a]
M. Serra, E. Bernardi, G. Marrubini, and L. Colombo
Department of Drug Sciences, Medicinal Chemistry and
Pharmaceutical Technology Section
University of Pavia
Viale Taramelli 12, 27100 Pavia, Italy
E-mail: massimo.serra@unipv.it
R
O
(i)
(ii)
O
O
PhSe
R
R
N
N
N
TFA
Ar
Ar
Ar
(i) PhSeCH2CHO
CO2H
NH2
dehydroxy
selenation
(ii)
functionalization
Fully deprotected,
R
one-pot vinylation
quaternary, a-vinyl AA's
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Scheme 1. Novel route to unprotected α-alkyl, α-vinyl α-amino acids
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10.1002/ejoc.201700353
European Journal of Organic Chemistry
FULL PAPER
O
O
OH
Ph
Three main considerations directed our efforts towards this
choice: a) the synthetic sequence, once optimized, could be
carried out one-pot; b) an enantioselective variant could be
devised through the use of a chiral base; c) a literature
precedent of a successful condensation between an oxazolone
enolate and aldehyde en route to β-hydroxy-α-aminoacids.11 In
addition, the vinyl moiety is more versatile than substituted
alkenyl groups if the terminal carbon is designed as point of
attachment for further functionalization or modification as, for
example, in the case of Heck reaction or alkene/alkyne
metathesis. In a paradigmatic example, a Heck reaction of a
quaternary amino acid carrying both a α-vinyl and a 1-methyl-2-
butenyl substituents involves only the former group.8f
O
OMs
(i)
(ii)
O
Ph
O
O
PhSe
PhSe
N
N
N
Ph
3
1
Ph
Ph
2
Ph
(iv)
(iii)
O
OAc
O
O
O
PhSe
5a,b
N
N
Ph
Ph
Ph
4
Ph
Scheme 2. One-pot vinylation of phenylalanine-derived azlactone 1. Reagents
and conditions: (i) PhSeCH2CHO, Et3N; (ii) MsCl, Et3N; (iii) Bu4NI, Δ; (iv) Ac2O,
DMAP.
Table 1. One-pot vinylation of azlactones: preliminary studiesa
Results and Discussion
Entry a
4 (%)d
Base
(equiv)
Aldol/DHSe
temp
Bu4NI
(equiv)
We started our investigations using the phenylalanine derived-
azlactone
1
(Scheme 2), which was treated with 2-
1 b
2
1.5
1.05
1.05
1.05
1.05
1.05
1.05
0.5
RT / RT
0°C / RT
-
-
20
27
24
46
45
36
54
56
42
(phenylseleno)acetaldehyde in the presence of triethylamine.
The aldol reaction proceeded smoothly at RT to give the
diastereoisomeric aldol adducts, which were converted in situ to
the corresponding mesylates
3
by treatment with
3
–10°C / RT
0°C / RT
-
methanesulfonyl chloride. After 24 hours, we isolated the
desired vinyl azlactone 4, although in low (20%) overall yield.
The monitoring of the reaction by TLC analysis showed the rapid
formation of the aldol adducts, while the obtainment of the
mesylate derivatives and, more significantly, the final elimination
step turned out to be slower. In order to get some insight on the
stereoselection of the relevant newly formed stereocenter
adjacent to the carbonyl function, we attempted to separate the
diastereoisomeric alcohols 2 by flash chromatography, but a
retro-aldol reaction promoted by silica gel chromatography was
observed. On the other hand, the chromatographic separation of
stable mesylates 3 was troublesome, giving in all cases
diastereoisomeric mixtures. Eventually we found that in situ
acetylation with acetic anhydride of the aldol adducts allowed an
easy separation of the two diastereoisomers 5a and 5b.
In anticipation of the feasible enantioselective variant of the
reaction, we tested catalytic amounts of a limited number of
chiral bases derived by cinchona alkaloids and found in some
cases a significant increase in the 5a/5b diastereomeric ratio.12
For example, the use of 20% of (DHQD)2PHAL raised the
diastereoisomeric excess from 24% to 80% and, more
importantly, the enantiomeric excess of both diastereoisomers,
determined by HPLC using a chiral stationary phase, was found
to be 64% for the minor diastereoisomer 5a, and slightly lower
for the major one 5b.
4
1
5
0°C / RT
2
6
0°C / RT
0.5
1
7
0°C / Reflux
0°C / Reflux
0°C / Reflux
8
1
9 c
0.5
1
[a] Reactions were performed in DCM on a 0.075–0.15 mmol scale (0.1 M),
using 1.0 equiv of oxazolone and 1.05 equiv of aldhehyde. The mesylation
step was performed with MsCl (4.5 equiv added in 3 portions, followed by an
equimolar amount of Et3N), The reaction mixture was reacted for 24 h. [b]
Reaction performed with 1.5 equiv of aldehyde. [c] The reaction time was 12
h. [d] Yield of isolated product 4 over 3 steps.
sub-stoichiometric ratio (0.5 equiv) had a detrimental effect
(entry 6). Heating the reaction mixture at reflux we observed a
further increase in the reaction yields, whose relative values
remained the same also by lowering the amount of base to 0.5
eq (entries 7 and 8). Attempts to shorten the reaction time,
keeping the other parameters unchanged, proved to be
ineffective (entry 9). Encouraged by these initial results, we
further proceeded to optimize the reaction conditions in order to
enhance, if possible, both the yield and the rate of the reaction
(Table 2). For this purpose, we decided to explore the use of
microwave-assisted heating in the dehydroxyselenation step.
The first attempts, performed applying a simple microwave
transfer protocol (2 h at 80°C vs. 24 h at reflux), gave the
desired vinyl azlactone 4 in quite low yields (Table 2, entry 1).
As shown by the results summarized in Table 2, the yields have
been considerably improved by increasing the temperature and
By assuming that the yield of the dehydroxyselenation reaction
might be increased by the use of a stronger nucleophile than the
chloride ion, which could be able to more efficiently attack the
selenium atom, we thought to employ tetrabutylammonium
iodide as
a source of iodide anions. In fact, adding a
stoichiometric amount of quaternary ammonium salt, yield was
raised to 46% (Table 1, entry 4). Experimentation showed that
increasing the amount of tetrabutyl ammonium iodide the yields
remained almost unchanged (entry 5), while its use in
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10.1002/ejoc.201700353
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CO2
Table 2. Screening of the optimal reaction conditionsa
R
NH3
1. PhSeCH2CHO
2. MsCl
3. Bu4NI, Δ MW
TFA
O
O
Entry
Solvent
Base
4 (%)d
TMAH, Cbz2O
CO2H
MW heating
temp (°C)
Time
10 R = Bn (98%)
11 R = Me (82%)
12 R = iPr (92%)
R
O
O
(min)
120
15
THF
N
N
Ph
Ph
1
2
DCM
DCM
DCE
MeCN
THF
TEA
TEA
TEA
TEA
TEA
TEA
DIEA
DBU
TEA
TEA
TEA
80
120
150
120
110
150
110
110
110
110
Reflux
23
57
17
13
82
60
21
0
1 R = Bn
2 R = Me
3 R = iPr
4 R = Bn (82%)
8 R = Me (62%)
9 R = iPr (71%)
R
NHCbz
13 R = Bn (96%)
14 R = Me (81%)
15 R = iPr (78%)
3
12
Scheme 3. Substrate scope and obtainment of fully deprotected and N-
protected α-vinyl quaternary amino acids
4
15
5
10
6
THF
10
Since a fast method for the obtainment of easy-to-functionalize
quaternary amino acids in an enantiopure fashion would be
highly desirable, we decided to perform
enantioselective variant of this synthetic protocol, focusing our
attention on the use of chiral bases in the enolate formation step.
For this purpose we thought to exploit the reactivity of the
commercially available Cinchona alkaloids I–VI,13 the thiourea-
based catalyst of Takemoto and co-workers VII,14 and the chiral
guanidines VIII–XI reported to catalyze a direct asymmetric aldol
reaction between 5H-oxazol-4-ones and aldehydes15 (Figure 1).
7
THF
10
a
study on
8
THF
10
9 b
10
11c
THF
10
20
75
80
PhCH3
THF
10
1440
[a] Reactions were executed on a 0.075–0.15 mmol scale (0.1 M) starting
from azlactone 1. The mesylation step was performed with MsCl (4.5 equiv
added in 3 portions, followed by an equimolar amount of Et3N), and the
elimination step was accomplished in the presence of 1.0 equiv of Bu4NI
applying microwave heating. [b] Reaction performed without Bu4NI. [c]
Reaction performed applying conventional heating. [d] Yield of isolated
product 4 over 3 steps.
CH3
H3
C
H3C
CH3
N
N
N
N
O
O
O
O
OCH3
OCH3
OCH3
OCH3 H3CO
H3CO
O
O
O
O
N
N
N
N
(DHQ)2AQN (I)
(DHQD)2AQN (II)
concurrent shortening the reaction time, reaching, in a few
minutes of MW heating, the same values obtained by
conventional heating (entry 2).
CH3
H3C
H3
C
CH3
N
N
N
N
N
N
N
N
O
O
O
O
OCH3 H3CO
H3CO
Switching the solvent to tetrahydrofuran the overall yield
reached a satisfactory 82% value (entry 5). Comparable
results were obtained working in toluene (entry 10), whereas
the use of acetonitrile gave low yields. With regard to the
base, triethylamine was superior to diisopropylethylamine and
stronger bases such as DBU. Finally control experiments were
performed as we have wondered whether the use of THF with
conventional heating would give the same or worse results
with respect to microwave heating. The obtainment of vinyl
azlactone 4 in almost the same yield (entry 11) clearly pointed
out that MW heating affects only the reaction rate.
N
N
N
N
(DHQ)2PHAL (III)
(DHQD)2PHAL (IV)
CH3
H3C
N
N
N
N
H3
C
CH3
N
O
O
O
O
N
N
OCH3
N
H3CO
H3CO
N
N
N
N
(DHQ)2PYR (V)
(DHQD)2PYR (VI)
CF3
Ph
Ph
S
N
N
Ph
Ph
OH
N
H
F3
C
N
H
N
H
N
H
N
OH
N
N
With the optimized one-pot protocol for the direct vinylation of
phenylalanine-derived azlactone in our hands, we proceeded
for a further investigation of the reaction substrate scope
(Scheme 2). Azlactones derived from alanine 6 and valine 7
reacted smoothly to give the corresponding vinyl azlactones 8
and 9 in 62% and 71% yields, respectively. To obtain free α-
vinyl α-amino acids, that may find useful applications in
peptide synthesis, we tried to open the oxazolone ring under
acidic conditions. Both the use of 6N HCl and trifluoroacetic
acid (TFA) worked well, although the latter gave the desired
fully deprotected quaternary amino acids in higher yields. For
the sake of completeness, we demonstrated that the free
amino acids could be easily converted into N-protected
derivatives, such as N-Cbz α-vinyl quaternary amino acids 13–
15 (Scheme 3).
(S,S) VII
VIII
IX
F3
C
CF3
F3
C
CF3
CF3
CF3
CF3
CF3
N
N
N
H
N
H
N
OH
N
OMe
X
XI
Figure 1. Chiral bases
When 2-phenyl-4-benzyl-5-oxazolone 1 was treated with 0.1
equivalents of the Sharpless ligand (DHQD)2PHAL (IV), the
vinylated product 4 was obtained in moderate enantioselectivity
(73% enantiomeric excess (ee)) and good overall yields (Table 3,
entry 1).
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10.1002/ejoc.201700353
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12,8c and comparing the optical rotations with literature values.
Table 3. Chiral protocol
Base
equiv
Aldol
temp
eeb
%
Entry
R =
Solvent
Base
ya %
It is worth mentioning that even if an efficient enantioselective
organocatalyzed aldol reaction between (4-substituted)-oxazol-
5-one enolates and aliphatic aldehydes was recently reported,11
to the best of our knowledge, herein we describe the first
example of this asymmetric transformation in the presence of an
α-functionalized aldehyde.
A decrease in the amount of base marginally affected the
enantioselectivity but brought about a substantial decrease in
the yield (entry 2), whereas the use of greater amounts of base
afforded the desired product in higher yields but in lower
enantiomeric ratio (entry 3). The dihydroquinidine-derived
ligands (DHQD)2AQN (II) and (DHQD)2PYR (VI) were shown to
be less efficient and afforded the vinyl azlactone with lower
enantioselectivity (ee 41–55%), while when we used the
1
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Me
Me
Me
Me
Me
iPr
iPr
iPr
iPr
iPr
THF
THF
IV
IV
IV
VI
II
0.1
0.025
0.6
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0 °C
0 °C
51
20
66
50
34
59
60
64
75
78
62
54
63
36
76
25
12
20
25
35
69
32
29
46
3
73
71
64
55
41
16
–18
–10
74
86
75
31
78
54
19
0
2
3
THF
0 °C
4
THF
0 °C
5
THF
0 °C
6
THF
III
V
0 °C
7
THF
0 °C
8
THF
I
0 °C
pseudoenantiomers
of
the
Sharpless
catalysts
the
9
PhCH3
PhCH3
PhCH3
PhCH3
Xylene
DCM
IV
IV
IV
IV
IV
IV
VII
VIII
IX
X
0 °C
enantioselectivities dropped dramatically (entries 6–8).
Furthermore, opposite sense of enantioselection was observed
with (DHQD)2PYR (V) and (DHD)2AQN (I) (entries 7 and 8).
Switching the solvent to toluene the ee remained almost
unchanged, but we observed a considerable increase of the
overall yield (entry 9). Gratifyingly, the use of (DHQD)2PHAL at –
10°C afforded the final vinyl oxazolone 3 in very good yield
(78%) and a satisfactory 86% ee (entry 10). Unfortunately, the
enantioselectivity did not improve upon a further decrease in the
temperature. The use of other aromatic solvents such as xylene
also gave comparable results in terms of yield and
enantioselectivity (entry 13), while employing chlorinated
solvents both the yield and the ee dropped down (entry 14). The
optimized conditions (toluene, (DHQD)2PHAL, –10°C) were then
applied in subsequent experiments in order to study the
reactivity of the commercially available Takemoto thiourea VII,
and the chiral guanidines VIII–XI, which were synthesized
following the reported procedures.15 Among these, only the
guanidine-based ligand IX furnished the desired product 4 in
good enantiomeric excess, albeit in low yield (entry 17). To
further examine the substrate scope of the reaction, the
experimentation was extended to alanine- and valine-derived
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
-10 °C
-30 °C
-78 °C
-10 °C
-10 °C
-10 °C
-10 °C
-10 °C
-10 °C
-10 °C
-10 °C
-10 °C
-10 °C
-10 °C
-10 °C
-10 °C
-10 °C
-10 °C
-10 °C
-10 °C
-10 °C
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
THF
79
30
0
XI
IV
IV
VI
II
46
55
43
49
30
7
PhCH3
THF
azlactones
6
and 7. The phthalazine-based ligand
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
THF
(DHQD)2PHAL showed to be the only one capable of inducing
an acceptable level of enantioselectivity, giving the vinyl
azlactones 8 and 9 with 55% (entry 21) and 45% (entry 26) ee’s
respectively.
A preliminary scale-up study of the vinylation reaction was
performed on the phenylalanine-derived azlactone 4 firstly
quadrupling, then increasing tenfold (up to 1 gram) the standard
amount of starting material. In both cases, we obtained the
desired products in very similar yields and ee’s. Comparable
results were obtained with alanine- and valine-derived
azlactones.
VII
IX
IV
VI
II
62
36
64
52
4
45
8
31
13
0
PhCH3
PhCH3
VII
IX
As a final proof of concept, we demonstrated that this novel
vinylation method could be used for the preparation of further
functionalizable quaternary amino acids with potential
applications in de novo peptide design and engineering;
therefore, a brief investigation on the reactivity of the installed
vinyl group was planned. By performing a Heck reaction in the
[a] Yield of isolated azlactones 4, 8, and 9 over 3 steps. [b] The ee’s were
determined by chiral HPLC under constant flow rate of 1 mL/min in isocratic
mode using 100% n-heptane as mobile phase. The absolute configurations
of the major enantiomers were determined to be S by converting azlactones
4, 8, and 9 into the corresponding zwitterionic amino acids 10,8c 11,16 and
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10.1002/ejoc.201700353
European Journal of Organic Chemistry
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desiccator, or flame-dried and cooled under inert atmosphere prior to use.
Liquid reagents and solvents were introduced by oven-dried syringes
through septa-sealed flasks under an inert atmosphere.
presence of 1-bromo-4-nitrobenzene and PdEnCat 30 (a
polyurea-encapsulated Pd(OAc)2 catalyst),17 the azlactone 4 was
easily converted into the N- and C-protected quaternary amino
acid 16 (Scheme 4), achieving at the same time the opening of
the oxazolone ring, the protection of the carboxylic function, and
the derivatization of the double bond.
NMR spectroscopic methods
O2N
Br
O2N
O
10% PdEnCat
Bu4NOAc
Nuclear magnetic resonance spectra were acquired at 400 MHz for 1H
and 100 MHz for 13C, using a Bruker Avance 400 MHz spectrometer
equipped with Bruker’s TopSpin 1.3 software package. The abbreviatons
s, d, t, q, br s, and m stand for the resonance multiplicities singlet,
doublet, triplet, quartet, broad singlet, and multiplet, respectively. In the
peak listing of 13C spectra abbreviations s and t refer to zero and two
protons attached to the carbons, as determined by DEPT-135
experiments. Sample temperatures were controlled with the variable-
temperature unit of the instrument.
O
CO2Me
N
MeOH
Δ MW 120°C
Ph
NHCOPh
Ph
4
Ph
(81%)
16
Scheme 4. Functionalization of the vinyl moiety
Conclusions
Chiral HPLC methods
In conclusion we have developed an efficient protocol for the
synthesis of quaternary α-vinyl-α-amino acids, exploiting a direct
one-pot vinylation of different azlactones. The key step is an
aldol addition with phenylseleno acetaldehyde, followed by a
dehydroxyselenation reaction. The final quaternary amino acids
were obtained in enantioenriched form (up to 86% ee) and good
overall yields (62–78%) by the use of catalytic Sharpless ligand
(DHQD)2PHAL in the aldol condensation step. It is worth to
mention that the optimized synthetic protocol can be performed
in gram-scale giving the final products in almost unchanged
yields and ee’s. Moreover, we demonstrated that the vinyl
moiety installed onto the oxazolone ring could be exploited for
the obtainment of further functionalized quaternary amino acids.
For details on the chiral HPLC separations see Supporting Information.
General procedure for the synthesis of oxazolones 1, 6, and 7
N-benzoyl amino acid was added portion-wise over 20 minutes to a
stirred solution of DCC (1 equiv) in dry DCM (0.3 M) under nitrogen
atmosphere at 0°C. Reaction completion was monitored by TLC analysis.
While keeping the reaction mixture at 0°C, a vacuum filtration with Gooch
apparatus was performed. The residue was washed with Et2O and the
solvent was evaporated in vacuo. Oxazolones 1, 6, and 7 were matched
with their reported data [19]
.
4-benzyl-2-phenyloxazol-5(4H)-one (1). The title compound was
prepared from N-benzoylphenylalanine (1 g, 3,71 mmol) according to the
general procedure. The crude mixture was purified by crystallization with
light petroleum ether to obtain 1 as white solid (746 mg, 80%).
Experimental Section
General Remarks
4-methyl-2-phenyloxazol-5(4H)-one (6). The title compound was
prepared from N-benzoylalanine (1 g, 5,17 mmol) according to the
general procedure. The crude mixture was purified by Kugelrohr
distillation (150°C, 0.01 mmHg) to obtain 6 as a white solid (680 mg,
75%).
All chemicals were of reagent grade and were used without further
purification. Solvents were purified according to the guidelines in
Purification of Laboratory Chemicals[18]. All solvents were freshly distilled
from the appropriate drying agent. THF and toluene were distilled from
sodium/benzophenone ketyl; TEA and DCM from CaH2. Reactions
requiring anhydrous conditions were performed under N2. Yields were
calculated for compounds purified by flash chromatography and judged
homogeneous by thin-layer chromatography, NMR, and mass
spectrometry. Thin layer chromatography was performed on Kieselgel 60
F254 (Merck) glass plate eluting with solvents indicated, visualized by a
254 nm UV lamp, and stained with aqueous ceric molybdate solution or
iodine and a solution of 4,4’-methylenebis-N,N-dimethylaniline, ninhydrin,
and KI in an aqueous ethanolic solution of AcOH. Flash chromatography
was performed on Merck Kieselgel 60 (230–400 mesh). Optical rotations
[α]D were measured in a cell of 5 cm path length and 1 mL capacity with
a Jasco DIP-1000 polarimeter. Infrared spectra were recorded on a
Perkin–Elmer ATR-FTIR 1600 series spectrometer using neat samples.
Mass spectra were acquired with an APEX II FT-ICR mass spectrometer
4-isopropyl-2-phenyloxazol-5(4H)-one (7). The title compound was
prepared from N-benzoylvaline (1 g, 4,52 mmol) according to the general
procedure. The product was purified by Kugelrohr distillation (165°C,
0.01 mmHg) to obtain 7 as a white solid (790 mg, 86%)
Synthesis of 4-methyl-2-phenyl-4-vinyloxazol-5(4H)-one (8)
To a solution of 4-methyl-2-phenyloxazol-5(4H)-one (6) (100 mg, 0.57
mmol) in dry THF (0.95 mL, 0.60 M) under nitrogen atmosphere, Et3N (40
µL, 0.29 mmol) was added and the reaction mixture was cooled at –10°C.
A solution of 2-(phenylselenyl)acetaldehyde (119 mg, 0.60 mmol) in dry
THF (1 mL, 0.60 M) was added and the reaction mixture was stirred for
0.5 h. Formation of the aldol adducts was monitored by TLC analysis, Rf
(Bruker Daltonics, Billerica, MA) equipped with
a
4.7 tesla
superconducting magnet (Magnex Scientific, Oxford, England).
Glassware for all reactions was oven-dried at 110 °C and cooled in a
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10.1002/ejoc.201700353
European Journal of Organic Chemistry
FULL PAPER
= 0.36 and Rf = 0.29 (hexane/AcOEt 85:15). Afterwards, methanesulfonyl
chloride (66 µL, 0.86 mmol) and Et3N (80 µL, 0.57 mmol) were added in
three portions at 10 minute intervals. After each addition, the pH was
monitored with litmus paper and, if necessary, Et3N was added to
maintain a basic pH during the reaction. Formation of the mesylates was
monitored by TLC analysis, Rf = 0.23 and Rf = 0.19 (hexane/AcOEt
80:20). After 10 minute from the last addition, tetrabutylammonium iodide
(207 mg, 0.57 mmol) was added and the reaction mixture was heated in
a microwave oven at 110°C for 10 minute in sealed vessel. The reaction
temperature was monitored by external surface sensor. After reaction
completion was monitored by TLC analysis, the mixture was washed with
phosphate buffer saturated with NaCl. The organic layer was dried with
anhydrous Na2SO4, filtered and evaporated in vacuo. The crude mixture
was purified by flash chromatography (SiO2; hexane/AcOEt 95:05) to
obtain 8 as a yellow oil (71 mg, 62 %).
Synthesis of 4-benzyl-2-phenyl-4-vinyloxazol-5(4H)-one (4)
To a solution of 4-benzyl-2-phenyloxazol-5(4H)-one (1) (100 mg, 0.40
mmol) in dry THF (0.67 mL, 0.6 M) under nitrogen atmosphere, Et3N (28
µL, 0.20 mmol) was added and the reaction mixture was cooled at –10°C.
A solution of 2-(phenylselenyl)acetaldehyde (83 mg, 0.42 mmol) in dry
THF (0.70 mL, 0.60 M) was added and the reaction mixture was stirred
for 0.5 h. Formation of the aldol adducts was monitored by TLC analysis,
Rf
=
0.36 and Rf
=
0.29 (hexane/AcOEt 85:15). Afterwards,
methanesulfonyl chloride (46 µL, 0.60 mmol) and Et3N (56 µL, 0.40
mmol) were added in three portions at 10 minute intervals. After each
addition, the pH was monitored with litmus paper and, if necessary, Et3N
was added to basify the solution. Formation of mesylates was monitored
with TLC analysis, Rf = 0.28 and Rf = 0.23 (hexane/AcOEt 80:20). After
10 minute from the last addition, tetrabutylammonium iodide (145 mg,
0.40 mmol) was added and the reaction mixture was heated in a
microwave oven at 110°C for 10 minute in sealed vessel. The reaction
temperature was monitored by external surface sensor. After reaction
completion, monitored by TLC analysis, the mixture was washed with
phosphate buffer saturated with NaCl. The organic layer was dried with
anhydrous Na2SO4, filtered and evaporated in vacuo. The crude mixture
was purified by flash chromatography (SiO2; hexane/AcOEt 95:05) to
obtain 4 as a yellow oil (89 mg, 82 %).
Chiral procedure: (DHQD)2PHAL (0.1 equiv) was used in the aldol
condensation step in place of Et3N (79 mg, 69 %). Rf
= 0.63
(hexane/AcOEt 95:5); IR (neat, cm-1) 3077, 2977, 2921, 2845, 1823,
1651, 1580, 1448; 1H NMR (CDCl3, 400 MHz) δ 1.66 (s, 3H), 5.29 (d, J =
10.5 Hz, 1H), 5.47 (d, J = 17.2 Hz, 1H), 6.02 (dd, J = 10.5, 17.2 Hz, 1H),
7.51 (app t, J = 7.5 Hz, 2H), 7.60 (app t, J = 7.5 Hz, 1H), 7.51 (app d, J =
7.5 Hz, 2H); 13C{1H} NMR (CDCl3, 100 MHz) δ 24.7, 70.6 (s), 117.2 (t),
126.3 (s), 128.4, 129.2, 133.3, 135.8, 160.7 (s), 178.9 (s); HRMS (ESI)
calculated for C12H11NNaO2 [M+Na] + 224.06820, found 224.06869 (Δ =
2.2 ppm).
Chiral procedure: (DHQD)2PHAL (0.10 equiv) was used in the aldol
condensation step in place of Et3N (87 mg, 78 %). Rf
= 0.63
(hexane/AcOEt 95:05); IR (neat, cm-1) 3031, 2917, 2848, 1815, 1654,
1
1580, 1450; H NMR (CDCl3, 400 MHz) δ 3.29 (s, 2H), 5.35 (d, J = 10.7
Hz, 1H), 5.55 (d, J = 17.2 Hz, 1H), 6.14 (dd, J = 10.5, 17.2 Hz, 1H), 7.14–
7.25 (m, 5H), 7.45 (app t, J = 7.8 Hz, 2H), 7.56 (app t, J = 7.5 Hz, 1H),
7.91 (app d, J = 7.8 Hz, 2H); 13C{1H} NMR (CDCl3, 100 MHz) δ 44.6 (t),
75.7 (s), 117.9 (t), 126.1 (s), 127.7, 128.3, 128.6, 129.1, 130.7, 133.1,
134.4 (s), 135.0, 160.5 (s), 177.8 (s); HRMS (ESI) calculated for
C18H15NNaO2 [M+Na] + 300.09950, found 300.10005 (Δ = 1.8 ppm).
Synthesis of 4-isopropyl-2-phenyl-4-vinyloxazol-5(4H)-one (9)
To a solution of 4-isopropyl-2-phenyloxazol-5(4H)-one (7) (100 mg, 0.49
mmol) in dry THF (0.82 mL, 0.60 M) under nitrogen atmosphere, Et3N (34
µL, 0.25 mmol) was added and the reaction mixture was cooled at –10°C.
A solution of 2-(phenylselenyl)acetaldehyde (103 mg, 0.52 mmol) in dry
THF (0.87 mL, 0.60 M) was added and the reaction mixture was stirred
for 0.5 h. Formation of the aldol adducts was monitored by TLC analysis,
Rf
=
0.36 and Rf
=
0.29 (hexane/AcOEt 85:15). Afterwards,
Synthesis of 1-(4-benzyl-5-oxo-2-phenyl-4,5-dihydrooxazol-4-yl)-2-
(phenylselanyl)ethyl acetates (5)
methanesulfonyl chloride (57 µL, 0.74 mmol) and Et3N (68 µL, 0.49
mmol) were added in three portions at 10 minute intervals. After each
addition, the pH was monitored with litmus paper and, if necessary, Et3N
was added to maintain a basic pH during the reaction. Formation of the
mesylates was monitored with TLC analysis, Rf = 0.32 and Rf = 0.40
(hexane/AcOEt 80:20). After 10 minute from the last addition,
tetrabutylammonium iodide (179 mg, 0.49 mmol) was added and the
reaction mixture was heated in a microwave oven at 110°C for 10 minute
in sealed vessel. The reaction temperature was monitored by external
surface sensor. After reaction completion, monitored by TLC analysis,
the mixture was washed with phosphate buffer saturated with NaCl. The
organic layer was dried with anhydrous Na2SO4, filtered and evaporated
in vacuo. The crude mixture was purified by flash chromatography (SiO2;
hexane/AcOEt 95:05) to obtain 9 as a yellow oil (81 mg, 71 %).
To a solution of 4-benzyl-2-phenyloxazol-5(4H)-one (1) (100 mg, 0.40
mmol) in dry solvent (0.67 mL, 0.60 M) under nitrogen atmosphere, Et3N
(28 µL, 0.20 mmol) was added and the reaction mixture was cooled at -
10°C. A solution of 2-(phenylselenyl)acetaldehyde (71 mg, 0.36 mmol) in
dry toluene (0.60 mL, 0.60 M) was added and the reaction mixture was
stirred for 0.5 h. Formation of alcohol intermediates 2 was monitored by
TLC analysis, Rf = 0.36 and Rf = 0.29 (hexane/AcOEt 85:15). Afterwards
acetic anhydride (226 µL, 2.40 mmol) and catalytic 4-
dimethylaminopyridine were added. The reaction mixture was allowed to
warm to room temperature. After reaction completion was monitored by
TLC analysis, a NaHCO3 saturated solution was added and the mixture
was extracted three times with DCM. The organic phases were collected,
dried with anhydrous Na2SO4, filtered and evaporated in vacuo. The
crude mixture was purified by flash chromatography (SiO2;
hexane/AcOEt 90:10) to obtain diastereoisomers 5.
Chiral procedure: (DHQD)2PHAL (0.10 equiv) was used in the aldol
condensation step in place of Et3N (71 mg, 62 %). Rf
= 0.63
(hexane/AcOEt 95:05); IR (neat, cm-1) 3062, 2969, 2934, 2876, 1822,
1806, 1654, 1580, 1451; 1H NMR (CDCl3, 400 MHz) δ 0.95 (d, J = 6.8 Hz,
3H), 1.10 (d, J = 6.8 Hz, 3H), 2.28 (septuplet, J = 6.8 Hz, 1H), 5.32 (dd, J
= 0.8, 10.5 Hz, 1H), 5.44 (dd, J = 0.8, 17.2 Hz, 1H), 6.01 (dd, J = 10.5,
17.2 Hz, 1H), 7.52 (app t, J = 7.8 Hz, 2H), 7.61 (app t, J = 7.5 Hz, 1H),
8.08 (app d, J = 7.8 Hz, 2H); 13C{1H} NMR (CDCl3, 100 MHz) δ 17.1,
17.3, 36.3, 78.0 (s), 118.0 (t), 126.3 8 (s), 128.4, 129.2, 133.1, 135.1,
160.6 (s), 178.7 (s); HRMS (ESI) calculated for C14H15NNaO2 [M+Na] +
252.09950, found 252.09999 (Δ = 1.9 ppm).
Diastereoisomer 5a
Colorless oil (59 mg, 30 %). Rf = 0.35 (hexane/AcOEt 90:10); IR (neat,
cm-1) 3058, 2925, 2845, 1818, 1738, 1648, 1578, 1451, 1208, 1050; 1H
NMR (CDCl3, 400 MHz) δ 1.98 (s, 3H), 3.15 (d, J = 13.1 Hz, 1H), 3.27 (d,
J = 13.1 Hz, 1H), 3.27–3.45 (m, 2H), 5.69 (dd, J1 = 3.1 Hz, J2 = 9.2 Hz,
1H), 7.08–7.20 (m, 5H), 7.26–7.35 (m, 3H), 7.46 (app t, J = 7.6 Hz, 2H),
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700353
European Journal of Organic Chemistry
FULL PAPER
7.53–7.64 (m, 3H), 7.87 (app d, J = 7.5 Hz, 2H); 13C{1H} NMR (CDCl3,
100 MHz) δ 21.1, 28.5 (t), 40.5 (t), 74.4, 78.0 (s), 125.8 (s), 127.9, 128.0,
128.4, 128.7, 129.1, 129.6, 130.0 (s), 130.6, 133.3 (s), 133.4, 133.8,
161.7 (s), 170.0 (s), 177.0 (s);; HRMS (ESI) calculated for
C26H23NNaO4Se [M+Na] + 516.07005, found 516.06925 (Δ = 1.6 ppm).
General procedure for the synthesis of N-Cbz-protected amino
acids (13–15).
To a solution of quaternary amino acid in dry CH3CN (0.10 M) under
nitrogen atmosphere, tetramethyl ammonium hydroxide monohydrate (2
equiv) was added. The reaction mixture was stirred for 45 minutes, then
Cbz2O (2 equiv) was added. Formation of the N-protected derivative was
monitored by TLC analysis. After reaction completion, the solvent was
evaporated in vacuo. The residue was recovered with a saturated
aqueous solution of Na2CO3 and washed three times with AcOEt. The
pH of the aqueous phase was adjusted to 1 with a HCl 1N solution, and
extracted three times with AcOEt. The organic layers were collected,
dried with anhydrous Na2SO4, filtered and evaporated in vacuo. Amino
Diastereoisomer 5b
Colorless oil (63 mg, 32%). Rf = 0.33 (hexane/AcOEt 90:10); IR (neat,
cm-1) 3060, 2961, 2923, 2850, 1806, 1746, 1651, 1577, 1451, 1217,
1045 ; 1H NMR (CDCl3, 400 MHz) δ 1.96 (s, 3H), 3.15 (d, J = 13.3 Hz,
1H), 3.24 (d, J = 13.3 Hz, 1H), 3.25 (dd, J1 = 3.4 Hz, J2 = 13.4 Hz, 1H),
3.35 (dd, J1 = 10.3 Hz, J2 = 13.4 Hz, 1H), 5.61 (dd, J1 = 3.4 Hz, J2 = 10.3
Hz, 1H), 7.12–7.17 (m, 5H), 7.26–7.31 (m, 3H), 7.43 (app t, J = 7.6 Hz,
2H), 7.52–7.59 (m, 3H), 7.81–7.86 (m, 2H); 13C{1H} NMR (CDCl3, 100
MHz) δ 21.0, 27.5 (t), 39.7 (t), 74.2, 77.2 (s), 125.5 (s), 127.9, 128.0,
128.4, 128.7, 129.2, 129.5 (s), 129.7, 130.6, 133.4, 133.5 (s), 133.7,
161.9 (s), 170.1 (s), 177.0 (s); HRMS (ESI) calculated for
C26H23NNaO4Se [M+Na] + 516.07005, found 516.06934 (Δ = 1.4 ppm).
acids 13, and 14 were matched with their reported data [7]
.
2-benzyl-2-(((benzyloxy)carbonyl)amino)but-3-enoic acid (13). The title
compound was prepared from 2-ammonio-2-benzylbut-3-enoate 10 (100
mg, 0.52 mmol) according to the general procedure. The crude mixture
was purified by Kugelrohr distillation (110°C, 0.01 mmHg) to obtain 13 as
a yellow oil (162 mg, 96%). Rf = 0.53 (DCM/MeOH 90:10 with 1% AcOH).
2-(((benzyloxy)carbonyl)amino)-2-methylbut-3-enoic acid (14). The title
compound was prepared from 2-ammonio-2-methylbut-3-enoate 11 (100
mg, 0.87 mmol) according to the general procedure. The crude mixture
was purified by Kugelrohr distillation (110°C, 0.01 mmHg) to obtain 14 as
a yellow oil (176 mg, 81 %).
General procedure for the synthesis of unprotected α-amino acids
(10–12)
4-vinyloxazol-5(4H)-one was dissolved in TFA/water 90:10 (0.05 M) and
heated to 100 °C for 12h. After reaction completion, the solvent was
evaporated in vacuo, the residue was recovered with water and washed
three times with DCM. The aqueous phase was evaporated in vacuo.
Amino acids 10, 11, and 12 were matched with their reported data [8c, 16]
.
Synthesis of 2-(((benzyloxy)carbonyl)amino)-2-isopropylbut-3-enoic
acid (15)
2-ammonio-2-benzylbut-3-enoate (10). The title compound was prepared
from 4-benzyl-2-phenyl-4-vinyloxazol-5(4H)-one 4 (100 mg, 0.36 mmol)
according to the general procedure. The crude mixture was purified by
ion-exchange chromatography with AMBERLITE IR-120(PLUS)® resin as
stationary phase. After the crude mixture was loaded onto the column,
the resin was washed with H2O until the eluted solution turned neutral,
then eluted with NH3 10% aqueous solution. The fractions containing the
product were evaporated in vacuo to afford 10 as a white solid (66 mg,
95%).
The title compound was prepared from 2-ammonio-2-isopropylbut-3-
enoate 12 (100 mg, 0.70 mmol) according to the general procedure. The
crude mixture was purified by Kugelrohr distillation (110°C, 0.01 mmHg)
to obtain 15 as a yellow oil (151 mg, 78%). Rf = 0.49 (DCM/MeOH 90:10
with 1% AcOH). IR (neat, cm-1) 3315, 3033, 2966, 2925, 2854, 1708,
1661, 1498, 1409, 1258, 1067; 1H NMR (CDCl3, 400 MHz) δ 0.96 (d, J =
6.9 Hz, 3H), 0.98 (d, J = 6.8 hz, 3H), 2.26 (m, 1H), 4.44–4.97 (br, 1H,
exchanges with D2O), 5.11 (d, J = 12.2 Hz, 1H), 5.15 (d, J = 12.2 Hz, 1H),
5.22 (d, J = 17.4 Hz, 1H), 5.29 (br s, 1H), 5.34 (d, J = 10.8 Hz, 1H), 6.26
(dd, J1 = 10.8 Hz, J2 = 17.4 Hz, 1H), 7.32–7.43 (m, 5H); 13C{1H} NMR
(CDCl3, 100 MHz) δ16.7, 17.3, 35.0, 67.0 (s), 67.1, 115.7 (t), 128.2 (2C),
128.5, 133.4, 135.9 (s), 155.4 (s), 175.5 (s); HRMS (ESI) calculated for
C15H18NO4 [M] – 276.12413, found 276.12368 (Δ = 1.6 ppm).
2-ammonio-2-methylbut-3-enoate (11). The title compound was prepared
from 4-methyl-2-phenyl-4-vinyloxazol-5(4H)-one 8 (100 mg, 0.50 mmol)
according to the general procedure. The crude mixture was purified by
ion-exchange chromatography with AMBERLITE IR-120(PLUS)® resin as
stationary phase. After the crude mixture was loaded onto the column,
the resin was washed with H2O until the eluted solution turned neutral,
then eluted with NH3 10% aqueous solution. The fractions containing the
product were evaporated in vacuo to afford 11 as a white solid (47 mg,
81%).
Synthesis
methyl
(E)-2-benzamido-2-benzyl-4-(4-nitrophenyl)but-3-
enoate (16). To a solution of 4-benzyl-2-phenyl-4-vinyloxazol-5(4H)-one
4 (100 mg, 0.36 mmol) in dry MeOH (3.6 mL, 0.10 M) under nitrogen
2-ammonio-2-isopropylbut-3-enoate (12). The title compound was
prepared from 4-isopropyl-2-phenyl-4-vinyloxazol-5(4H)-one 9 (100 mg,
0.44 mmol) according to the general procedure. The crude mixture was
purified by ion-exchange chromatography with AMBERLITE IR-
120(PLUS)® resin as stationary phase. After the crude mixture was
loaded onto the column, the resin was washed with H2O until the eluted
solution turned neutral, then eluted with NH3 10% aqueous solution. The
fractions containing the product were evaporated in vacuo to afford 12 as
a white solid (57 mg, 91%).
atmosphere,
1-bromo-4-nitrobenzene
(80
mg,
0.40
mmol),
tetrabutylammonium acetate (326 mg, 1.08 mmol) and Pd EnCat® (90
mg, 0.036 mmol) were added. The reaction mixture was heated in a
microwave oven at 120°C for 45 minute. Reaction completion was
monitored by TLC analysis, Rf = 0.39 (hexane/AcOEt 70:30). The
reaction mixture was filtered with Gooch funnel to remove Pd EnCat®.
The solvent was evaporated in vacuo, and the residue was recovered
with AcOEt and washed two times with water. The organic layer was
dried with anhydrous Na2SO4, filtered and evaporated in vacuo. The
crude mixture was purified by flash chromatography (SiO2;
hexane/AcOEt 75:25) to obtain 16 as a yellow oil (126 mg, 81%). The
product was matched with its reported data [20]
.
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10.1002/ejoc.201700353
European Journal of Organic Chemistry
FULL PAPER
azlactone intermediates generated in-situ from unprotected amino acids
see: i) M. Weber, R. Peters, J. Org. Chem. 2012, 77, 10846–10855.
P. Finkbeiner, N. M. Weckenmann, B. J. Nachtsheim, Org Lett. 2014,
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Acknowledgements
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[7]
[8]
Financial support from Italian Ministry of Education, University
and Research (MIUR) is gratefully acknowledged (PRIN project
2010NRREPL).
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Keywords: • α,α-disubstituted amino acids • aldol condensation
• quaternary stereocenter • oxazolones • one-pot vinylation
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10.1002/ejoc.201700353
European Journal of Organic Chemistry
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Quaternary amino acids
Massimo Serra,* Eric Bernardi, Giorgio
Marrubini, and Lino Colombo*
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One-pot vinylation of azlactones: fast
access to enantioenriched α-vinyl
quaternary amino acids
Here we report an efficient protocol for the synthesis of quaternary α-vinyl-α-amino
acids, exploiting a direct one-pot vinylation of different azlactones. The key step is
an aldol addition with phenylseleno acetaldehyde, followed by
a
dehydroxyselenation reaction. The final quaternary amino acids were obtained in
enantioenriched form (up to 86% ee) and good overall yields (62–78%) by the use
of catalytic Sharpless ligand (DHQD)2PHAL in the aldol addition step.
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