Absolute asymmetric synthesis of tertiary α-amino acids

Article abstract of DOI:10.1002/anie.201200950

Frozen: The spontaneous crystallization of an achiral compound in a chiral conformation is used as the unique source of chirality in an absolute asymmetric synthesis of tertiary amino acids. The dynamic axial chirality of tertiary aromatic amides is frozen in a crystal (see picture) and is responsible for the stereoselectivity of the deprotonation/alkylation (see scheme). α-Amino acid derivatives are synthesized in up to 96% ee. Copyright

Full text of DOI:10.1002/anie.201200950

Angewandte
Chemie
DOI: 10.1002/anie.201200950
Synthetic Methods
Absolute Asymmetric Synthesis of Tertiary a-Amino Acids**
Thi Thoa Mai, Mathieu Branca, Didier Gori, Rꢀgis Guillot, Cyrille Kouklovsky, and
Valꢀrie Alezra*
The synthesis of one enantiomer in the absence of any chiral
substance is a major challenge and very attractive from both
economical and conceptual points of view. This type of
synthesis has been termed absolute asymmetric synthesis.
Nevertheless, few examples of absolute asymmetric synthesis
have been described to date.[1] Several approaches have been
developed, for instance irradiation with circularly polarized
light,[2] or application of rotational and magnetic forces,[3] or
attrition-enhanced deracemization.[4] The most exemplified
approach in organic synthesis is probably the use of chiral
crystals of achiral or racemic compounds.[5] In that case, the
chiral crystals arise from spontaneous crystallization of
achiral compounds in a chiral conformation or from macro-
scopic chiral arrangement in crystals of racemic compounds.
These chiral crystals can be inorganic or organic and are used
in absolute asymmetric synthesis either as reactant[6] or
catalyst.[7] Owing to the constraints generated by the use of
crystals, only a limited number of organic reactions have been
reported to date, mostly in the field of photochemical
cycloaddition[8] or asymmetric autocatalysis.[9] To retain the
chirality of the crystal and prevent racemization of the
conformation, the reaction is often performed in solid state or
after dissolution at low temperature. This latter concept has
been named “frozen chirality”.[10]
For a few years we have been interested in the develop-
ment of asymmetric syntheses of nonproteinogenic amino
acids starting from natural a-amino acids.[11] Based on our
previous results,[11a–c] we wanted to tackle the great challenge
of the absolute asymmetric synthesis of tertiary a-amino acids
by exploiting the frozen-chirality concept. Herein, we de-
scribe for the first time a practical absolute asymmetric
synthesis of tertiary a-amino acid derivatives with enantio-
meric excesses up to 96% by starting from glycine, which is an
achiral compound. The synthesis involves a two-step reaction
(deprotonation–alkylation), using the homochirality of the
starting crystal as the unique source of stereoinduction.
Our strategy relies on the use of the axial chirality of
tertiary aromatic amides.[12] These compounds are generally
ꢀ
not planar around the Ar CO bond, and even moderate steric
hindrance induces a dihedral angle of 908. Depending on the
substitution pattern (A ¼ B; Scheme 1) these compounds can
Scheme 1. General strategy of absolute asymmetric synthesis of terti-
ary a-amino acids.
therefore present axial chirality. This strategy (Scheme 1)
requires the preparation of an oxazolidinone derived from
glycine and the growth of a chiral crystal made up of only one
ꢀ
enantiomer (axial chirality along the Ar CO bond). Disso-
lution at low temperature should prevent rotation and
subsequent racemization. Hence, this axial frozen chirality
should be retained, thereby inducing stereoselective attack by
electrophiles. After deprotection, various enantioenriched
tertiary natural or unnatural a-amino acids would be obtained
in few steps.
[*] T. T. Mai, Dr. M. Branca, D. Gori, Dr. R. Guillot, Prof. C. Kouklovsky,
Dr. V. Alezra
After several attempts, we found that oxazolidinone
1 (A = H, B = Ph, R = Me in Scheme 1; prepared in one
step from sodium glycinate) crystallized in the chiral space
group P212121 (Figure 1). A single crystal can be either aR or
Univ. Paris-Sud, Laboratoire de Chimie des Procꢀdꢀs et Substances
Naturelles, ICMMO
UMR 8182, CNRS, Bꢁt 410, 91405 Orsay (France)
E-mail: valerie.alezra@u-psud.fr
ꢀ
aS (axial chirality along the Ar CO bond) with a 50%
Homepage: http://www.icmmo.u-psud.fr
probability; both crystalline enantiomers are obtained during
the same crystallization procedure. Analysis of the crystallo-
graphic structure shows that the ortho-phenyl group is
oriented towards the acidic protons and that it hinders one
of the two prochiral acidic protons (the dihedral angle
between the carbonyl group and the aromatic group is
1138). Therefore, this compound seemed suitable for the
planned strategy. Despite some reproducibility problems,
preliminary trials showed that small crystals of this compound
[**] We thank the Ministꢂre de la Recherche et de l’enseignement
supꢀrieur (doctoral grant to M.B.) and the ANR (Agence Nationale
de la Recherche; ANR grant n8ANR-08-JCJC0099, doctoral grant to
T.T.M.) for financial support. The authors thank Dr. David Berardan
(ICMMO) for assistance and loan of planetary ball mill and Dr.
Susannah Coote for assistance with the English-language editing of
the manuscript.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200950.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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Angewandte
Communications
tion of cosolvents showed that dimethoxyethane (DME)
was the most appropriate (N,N,N’,N’-tetramethyl-ethane-1,2-
diamine (TMEDA) or 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinone (DMPU) did not improve the results). To
ensure a rapid reaction without racemization of the initial
crystal (after dissolution) or of the intermediate enolate (both
issues must be avoided), the following procedure was
adopted: a precooled solution of base, solvents, cosolvents,
and, if possible, the electrophile was prepared, and this
solution was added through a cannula directly onto the
powdered crystals of oxazolidinone 1 (also cooled to ꢀ788C).
To limit the racemization of the enolate, reactive benzylic
electrophiles (with iodide as leaving group) were chosen. We
favored electrophiles that could give access to biologically
relevant compounds (electrophile 2a should give access to
meta-tyrosine,[13] 2b to a potentially interesting analogue of
phenylalanine,[14] and piperonyl iodide to 3,4-dihydroxyphe-
nylalanine (DOPA)). For each electrophile, the cosolvent
quantity, the grinding type for the substrate (manual or by ball
mill), and the conditions of the reaction (concentration,
deprotonation time, or alkylation time) were then screened
(Table 1).
Figure 1. Compound 1: a) Picture of crystal growth, b) picture of
a large crystal of compound 1 stuck on the capillary (scale in cm),
c) synthesis (MS=molecular sieves), d) picture of a small crystal
superimposed with crystallographic structure (O red, N blue, H white).
can be alkylated with enantiomeric
excesses up to 61%. Then, we
decided to change the crystalliza-
Table 1: Screening of reaction conditions for alkylation of oxazolidinone 1.[a]
tion procedure. Small crystals of
compound 1 were formed in diethyl
ether and quality-checked under
polarized light in a binocular micro-
scope. A polarization microscope is
the most convenient tool for ana-
lyzing the quality and size of crys-
tals: normally, a good single crystal
is well-shaped with visible planar
faces and extinction of polarized
light is uniform; consequently the
crystal is exempt from defects or
twinning problems. After this selec-
tion, a small crystal was stuck onto
a capillary, dipped in a saturated
solution of compound 1, and
allowed to stir gently for a couple
of weeks for crystal growth.
Entry Electrophile Grinding[b] n equiv of V [mL]
t1 [min] t2 [min] Prod. Yield[c] [%] ee[d] [%]
E-I
DME
THF
1
2
3
4
5
6
7
M
M
M
M
M
M
PBM
2.1
2.1
2.1
30
0
2.1
30
5
5
1
1.2
1.2
1
0
0
0
0
0
0
0
10
10
10
10
10
45 (60) 72 (72)
[e]
(65)
(42)
(58)
(42)
(20)
(88)
(88)
(83)
3a
180
10
64 (99)[f] 73 (74)
1.2
48 (74)
96
8
9
10
11
12
M
2.1
2.1
2.1
30
1.2
1.2
1.2
1.2
5
0.5[g]
0.5
9.5
9.5
18
68
82
80
PBM
PBM
PBM
PBM
0.33
0.5
0.5
9.67 3b
9.5
9.5
70
(90)
(98)
90
(50)
(30)
ꢀ
Because rotation about the Ar
30
CO bond is very rapid (racemiza-
tion of the crystal occurs almost
instantaneously after dissolution at
room temperature), we are able to
recrystallize the major part of the
solution. Thus, a defect-free crystal
of 2 g can be obtained after three
weeks. After grinding into a thin
powder, optimization of the alkyla-
tion step was undertaken.
13
14
15
16
M
M
PBM
PBM
2.1
2.1
2.1
2.1
1.2
5
1.2
5
0
0
0
0
10
(21)
(37)
50
(94)
(93)
83
10
10
10
3c
57
87
[a] Unless specified, a precooled solution of KHMDS (2 equiv, 0.7m in toluene) and additive in THF was
added through a cannula at ꢀ788C to the powdered crystals of 1 (0.135 mmol). After t1 min (t1 =0
means that the electrophile is in the same solution as the base), electrophile 2 (5 equiv) was added and
the mixture allowed to stir for t2 min at ꢀ788C. [b] M=manual grinding and PBM=grinding with
a planetary ball mill of crystals of compound 1. [c] Yields in brackets correspond to conversion,
determined on the crude product by HPLC. [d] Enantiomeric excesses were determined by HPLC using
a chiral stationary phase. ee values in brackets are determined on the crude product. Racemic mixture for
HPLC references were synthesized by alkylation after previous dissolution of the crystals 1 at room
temperature. [e] Reaction was performed without toluene. [f] Significant amount of dialkylated product
was observed. [g] Since reaction occurred between the electrophile and the base, the electrophile was
Preliminary results showed that
the optimal solvent was tetrahydro-
furan (THF), and the optimal base
was potassium hexamethyldisilyl-
amide (KHMDS). The investiga- added soon after the base.
2
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In almost all cases, high enantioselectivities can be
reached but sometimes with rather low conversions. This is
due to the low solubilization of the starting crystals: at the end
of some experiments, white powder was still present in the
reaction medium. Several approaches were envisaged to limit
this problem: optimization of solvents and solubility (use of
larger amount of solvents or modification of the solvents and
cosolvents), increase of the alkylation time, and reduction of
the size of the powder particles by grinding the crystals of
compound 1 with a planetary ball mill. The comparison
between entries 2, 4, and 5 shows that the presence of toluene
and DME is necessary to give a high ee (moreover, reaction
without THF, only DME, showed almost no alkylated
product). Depending on the electrophile, more or less either
DME or THF is beneficial to the reaction (compare entries 1
and 3, 3 and 4, 10 to 12, 13 and 14, and 15 and 16). On the one
hand, an increase of the alkylation time did not have the
expected effect (entry 6): it induced a second deprotonation
of the alkylated compound 3a (easier to deprotonate
compared to crystals of 1, because 3a is already in solution),
thereby resulting in racemization of 3a and/or formation of
dialkylated compound. On the other hand, the use of
a planetary ball mill was very effective, and it slightly
improved the conversions (compare entries 4 and 7, 8 and 9,
13 and 15, 14 and 16). Optimized conditions led to the
alkylated products with enantioselectivities from 87 to 96%
and yields from 48 to 70%. Moreover, recrystallization of
compound 3b in a mixture of THF and pentane afforded
enantiopure crystals (ee > 99%, yield = 55%). Several recrys-
tallizations of this compound were performed on different
samples, and crystallographic analysis was carried out on the
enantiomer that possesses the longest retention time (using
HPLC with a chiral stationary phase). The absolute config-
uration of this enantiomer was given by crystallographic
structure determination (R configuration). For practical rea-
sons, the following steps were performed on the other
enantiomer (S configuration; this enantiomer has the shortest
retention time).
The next step was deprotection to access enantiopure
amino acids or close derivatives. To avoid racemization, the
reaction conditions had to be very mild. After optimization,
we succeeded in deprotecting compound (S)-3b in three steps
under mild conditions (Scheme 2). Thus, basic hydrolysis of
the oxazolidinone ring and subsequent esterification gave the
corresponding methyl ester (S)-4. Formation of an ester was
necessary to perform reduction of the amide with Schwartzꢀs
reagent,[15] which led to an imine that was hydrolyzed under
acidic conditions.
Hence, we succeeded in the absolute asymmetric synthesis
of enantiopure amino ester 5. From a synthetic point of view,
it is essential to know which enantiomer the synthetic
sequence will give access to and thus to choose the initial
crystal. Obviously, during the initial formation of small
crystals of compound 1, crystals of both enantiomers will be
present at the same time in one flask. We envisaged that the
sorting of these small crystals (aR and aS), if possible, would
allow us to choose the desired enantiomer for the synthesis.
Careful examination of the crystals did not show any notable
differences, such as those observed by Pasteur in crystals of
Scheme 2. Deprotection of compound (S)-3b to give enantiopure
amino ester (S)-5. TMS=trimethylsilyl, Cp=cyclopentadienyl.
tartaric acid derivatives. Nevertheless, when we observed the
small oriented crystals under polarized light,[16] we were able
to sort the positive crystals, which induced light extinction
when turned right, from the negative ones, which induced
light extinction when turned left. Alkylation under the
optimized conditions was repeated three times on crystals of
each sign (on small crystals and once on a large crystal, after
crystal growth) to give either enantiomer of compound 3b.
Analysis of compounds 3b by HPLC using a chiral stationary
phase confirmed that positive crystals gave access to the
R enantiomer (as determined by crystallographic structure),
and negative ones gave access to the opposite enantiomer.
Thus, we have demonstrated that we are able to choose the
appropriate crystal to obtain the desired enantiomer of
compound 5.
Concerning the stereoinduction of the reaction, it seems
very likely that alkylation occurs opposite to the aromatic
substituent. However, to prove this hypothesis, the absolute
ꢀ
configuration (axial chirality around the Ar CO bond) of the
starting oxazolidinone 1 in the crystal still has to be
determined. As the Flack parameter is not well-solved to
provide an answer, vibrational circular dichroism[17] is under
investigation to unravel this configuration. Preliminary results
confirm the stereoinduction.
In conclusion, we demonstrated the successful absolute
asymmetric synthesis of tertiary a-amino acid derivatives with
high enantiomeric excesses, without using any chiral com-
pound, but by using only frozen chirality of chiral crystals. The
amino acid derivatives are obtained through a complex
asymmetric two-step reaction (deprotonation and alkylation),
during which the dynamic axial chirality is retained. The
application of this work has allowed us to carry out the
synthesis of an enantiopure a-amino ester. To our knowledge,
this is the first example of the use of the frozen-chirality
approach for the synthesis of biologically interesting com-
pounds. Moreover, we have demonstrated that the frozen
chirality of tertiary aromatic amides can efficiently serve as
stereoinducer for alkylation. Finally, we are able to control
the configuration of the final product by carefully sorting the
initial crystals. We showed thus the usefulness of chiral
crystals in organic reaction after sorting them under polarized
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Received: February 3, 2012
Published online: && &&, &&&&
Keywords: amino acids · amides · asymmetric synthesis ·
.
chirality · synthetic methods
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4
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Synthetic Methods
T. T. Mai, M. Branca, D. Gori, R. Guillot,
C. Kouklovsky, V. Alezra*
&&&& — &&&&
Absolute Asymmetric Synthesis of
Tertiary a-Amino Acids
Frozen: The spontaneous crystallization
of an achiral compound in a chiral con-
formation is used as unique source of
chirality in an absolute asymmetric syn-
thesis of tertiary amino acids. The
amides is frozen in a crystal (see picture)
and is responsible for the stereoselectiv-
ity of the deprotonation/alkylation (see
scheme). a-Amino acid derivatives are
synthesized in up to 96% ee.
dynamic axial chirality of tertiary aromatic
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!