Frozen Chirality of Tertiary Aromatic Amides: Access to Enantioenriched Tertiary α-Amino Acid or Amino Alcohol without Chiral Reagent

Article abstract of DOI:10.1002/chem.201700110

One of the fundamental and intriguing aspects of life is the homochirality of the essential molecules. In this field, the absolute asymmetric synthesis of α-amino acids is a major challenge. Herein, we report access, by chemical means, to tertiary α-amino acid derivatives in up to 96 % ee without using any chiral reagent. In our strategy, the dynamic axial chirality of tertiary aromatic amides is frozen in a crystal and is responsible for the stereoselectivity of the subsequent steps. Furthermore, we could control the configuration of the final product by manually sorting and selecting the initial crystals. Based on vibrational circular dichroism studies, we could rationalize the observed stereoselectivity.

Full text of DOI:10.1002/chem.201700110

A Journal of
Accepted Article
Title: Frozen Chirality of Tertiary Aromatic Amides: Access to
Enantioenriched Tertiary α-Amino acid or Amino-Alcohol without
any Chiral Reagent.
Authors: Thi Thoa Mai, Baby Viswambharan, Didier Gori, Régis guillot,
Jean-Valère Naubron, Cyrille Kouklovsky, and Valérie Alezra
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To be cited as: Chem. Eur. J. 10.1002/chem.201700110
Link to VoR: http://dx.doi.org/10.1002/chem.201700110
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Frozen Chirality of Tertiary Aromatic Amides:
Access to Enantioenriched Tertiary -Amino acid or Amino-
Alcohol without any Chiral Reagent.
Thi Thoa Mai,[a] Baby Viswambharan,[a] Didier Gori,[a] Régis Guillot,[a] Jean-Valère Naubron, [b] Cyrille
Kouklovsky,[a] and Valérie Alezra*[a]
Abstract: One of the fundamental and intriguing aspects of life is the
homochirality of the essential molecules. In this field, the absolute
asymmetric synthesis of -amino acids is a major challenge. Herein
we report access, by chemical means, to tertiary -amino acids
derivatives in up to 96% ee without using any chiral reagent. In our
strategy, the dynamic axial chirality of tertiary aromatic amides is
frozen in a crystal and is responsible for the stereoselectivity of the
subsequent steps. Furthermore, we are able to control the
configuration of the final product by carefully sorting out the initial
crystals. Thanks to VCD studies, we were able to rationalize the
observed stereoselectivity.
crystallize in a macroscopic chiral arrangement (like racemic o-
tyrosine).[11] These chiral crystals (organic or inorganic) are
either employed as reactant[12–14] or catalyst,[15] and frequently
used in the fields of photochemical cycloaddition[16,17] or
asymmetric autocatalysis.[18–21] To avoid racemization in solution
of the conformational chirality fixed in the crystal, the reactions
are often performed in the solid state. In some cases, reactions
may be performed in solution, but after dissolution of the crystal
at low temperature. In that case, the chirality is “frozen”.
According to this concept, several reactions have been
performed,
besides
photocycloaddition,[22–25]
such
as
nucleophilic addition,[26] nucleophilic aromatic substitution,[27]
kinetic resolution[28] and even a two step reaction.[29]
Our research group has developed for a few years several
asymmetric syntheses of non proteinogenic amino acids starting
from natural -amino acids and using as the unique source of
chirality the initial chirality of the reacting -amino acid. We have
thus synthesized enantiopure -diamino acids through a
classical diastereoselective synthesis[30–34] and quaternary -
amino acids relying on the Memory of Chirality (MOC)[35]
principle.[36–39] The next step was the extension of this latter
methodology to the great challenge of absolute asymmetric
synthesis of tertiary -amino acids, i.e. to get rid of the initial
chirality and to start from the simplest achiral -amino acid,
glycine. We thus exploited the frozen chirality principle and
Introduction
The origin of homochirality of biomolecules continues to be a
intriguing question. Indeed, the synthesis of an enantioenriched
product from achiral precursors without the intervention of pre-
existing optical activity, is a major challenge named absolute
asymmetric synthesis. Although this is a very exciting concept,
there are only a limited number of absolute asymmetric
syntheses known today.[1,2] In order to induce symmetry-
breaking, several means have been used, such as irradiation
with circularly polarized light,[3–6] or application of rotational and
magnetic forces,[7] or attrition-enhanced deracemization.[8] The
most popular approach so far consists in using chiral crystals of
achiral or racemic compounds.[9,10] In fact, it is well known that
an achiral compound can spontaneously crystallize in
described in
a
preliminary communication[40] the absolute
asymmetric synthesis of tertiary -amino acid derivatives with
enantiomeric excesses up to 96%. Herein, we describe the
complete study, as well as the synthesis of amino alcohol and
we propose an explanation to the observed stereoselectivity
thanks to VCD and NMR studies.
enantiomorphous
dibenzoylperoxide), or very rarely that a racemic compound can
space
groups
(like
NaClO3
or
As for our MOC synthesis, we wanted to use the dynamic axial
chirality of tertiary aromatic amides.[41–43] This chirality relies on
the fact that the rotation around the Ar-CO bond (and around the
N-CO bond) is slow, and that the compound is not planar around
this bond (due to steric hindrance, the dihedral angle can be
close to 90°). Our strategy is depicted in Scheme 1: starting
from glycine, we could synthesize an oxazolidinone which
should possess a tertiary amide function. The challenge would
be to find the appropriate oxazolidinone that would crystallize as
a single enantiomer in a chiral conformation. Then, during
dissolution of this chiral crystal at low temperature, this “frozen
chirality” should be retained and induce a stereoselective
sequence deprotonation/alkylation. Deprotection should lead to
enantioenriched tertiary -amino acids, either proteinogenic or
non proteinogenic.
[a]
Dr. T.T. Mai, Dr. B. Viswambharan, D. Gori, Dr. R. Guillot, Prof. Dr.
C. Kouklovsky, Dr. V. Alezra
Univ. Paris-Sud,
Laboratoire de Méthodologie, Synthèse et Molécules
Thérapeutiques, ICMMO, UMR 8182, CNRS,
Université Paris-Saclay, Bât 410,
Orsay, F-91405 France
E-mail: valerie.alezra@u-psud.fr
Dr. J.-V. Naubron
[b]
Aix Marseille Université, Centrale Marseille,
CNRS - Spectropole, FR1739,
F- 13397 Marseille, France
Supporting information for this article is available. It contains
procedures and characterization data of all new compounds, NMR
spectra for VT studies, procedure for IR and VCD measurements,
DFT study, crystallographic tables. CCDC 904615 – 904622
contains the supplementary crystallographic data for this paper.
These data are provided free of charge by The Cambridge
Crystallographic Data Centre.
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Table 1. Synthesis of oxazolidinones 3 with R = CF3
Entry
1
ArCOX
Prod.
Yield (%)
58
Crystal
3a
Unstable
Compound[a]
2
3
4
3b
3c
3d
14
0
Unstable
Compound[a]
Scheme 1. General strategy of absolute asymmetric synthesis of tertiary -
amino acids.
Results and Discussion
81
Rac. (space group
Synthesis of an oxazolidinone, chiral in solid state
P-1)
The first step of our strategy was the synthesis of an
oxazolidinone which should crystallize in a chiral space group
and thus possess in a single crystal the same spatial orientation
(M or P configuration) for the aromatic moiety. From our
previous experience, we knew that this kind of compounds is
very often crystalline but the question of the chiral crystallization
was a matter of luck. We therefore considered several R groups
(corresponding to several ketones) and several aroyl chlorides.
We decided to favor first a high steric hindrance for R group, in
order to minimize the rotation about the amide bond.
5
3e
82
Chiral (space group
P212121)
[a] degradation led to the aroylated glycine.
We
first
envisaged
oxazolidinones
arising
from
hexafluoroacetone because this kind of oxazolidinones has been
already described.[44] Moreover, this should give access to the
unsubstituted oxazolidinone 1, which could be further
functionalized with various aroyl chlorides. We use
Unfortunately, this type of compounds was not very stable.
Compounds 3a and 3b led to the aroylated glycine (we were
surprised to obtain the crystallographic structure of this opened
compound 4 for oxazolidinone 3b). Compound 3c could not be
synthesized by this way and compound 3d gave a racemic
crystal (Figure 1). Only oxazolidinone 3e crystallized in a chiral
space group. It should be mentioned that in these two latter
cases, the amide oxygen is oriented toward the two
trifluoromethyl groups and the aromatic moiety toward the labile
proton, as expected.[47] We thus tried to deprotonate compound
3e with KHMDS and to add allyliodide to the enolate. This led to
the expected allylated product but along with significant
degradation. We then turned our attention to other
oxazolidinones.
hexafluoroacetone as
a reactant and performed in situ
dehydration with concentrated sulfuric acid.[45] This gave the
expected oxazolidinone 1 in 39% yield.[46] Heating at 85 °C in
THF with naphthoyl chloride or with compounds 2 and thionyl
chloride gave reasonable quantities of expected oxazolidinone 3
(Table 1).
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3
4
7c
7d
9
Rac. (space group
P21/c)
41
Rac. (space group
Pbca)
Figure 1. Crystallographic structures of compounds 4, 3d (racemic) and 3e
(chiral crystal).
We next synthesized oxazolidinones arising from benzophenone.
As the corresponding imine 5 (with an ester group) was
commercially available, we decided to first saponify the ester
(without hydrolyzing the imine function). This was achieved by
using solid KOH and only a few drops of water. The resulting
potassium salt 6 reacted then with an aroyl chloride in the
presence of trimethylaluminium (Table 2). Unfortunately, in this
series, all compounds crystallized in a racemic manner (Figure
2).
Table 2. Synthesis of oxazolidinones 7 with R = Ph
Entry
1
ArCOCl
Prod.
Yield (%)
22
Crystal
7a
Rac. (space group
Pna21)
2
7b
10
Rac. (space group
P21/c)
Figure 2. Crystallographic structures of compounds 7a-d (racemic).
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Since our attempts to use hindered R groups were unsuccessful,
we tried also to use formaldehyde to build an oxazolidinone. We
reasoned that, as we targeted glycine derivatives, we could be
lucky and observe in the crystallographic structure, the aromatic
moiety oriented toward the labile proton. To compensate the
decrease in the rotation barrier, we chose a hindered aroyl
chloride. Oxazolidinone 9 was thus synthesized in two steps in
very low yield (Scheme 2). Unfortunately, the aromatic moiety
was oriented on the wrong side (it is not on the same side as the
acidic proton and consequently on the side of the asymmetric
reaction) and the crystal was racemic (Figure 3). We then gave
up this series.
Figure 4. Crystallographic structure of compound 10 (chiral space group
P212121).
This oxazolidinone was tested in alkylation reactions with allyl
iodide. Preliminary results (deprotonation by 1.5 equiv. of
KHMDS in toluene, with 3 equiv. of DME in THF at -78 °C for 3
minutes, and then addition of 5 equiv. of allyl iodide at -78 °C for
10 minutes) showed that the allylated compound could be
obtained in enantiomeric excess up to 61% (yield = 18%).
Encouraged by this result, we selected this oxazolidinone for
further studies. Several attempts were thus made to improve its
synthesis. Two issues were identified: the glycinate salt was not
very soluble in acetone and the o-phenylbenzoyl chloride was
prone to form fluorenone via an electrophilic aromatic
substitution. Unfortunately, change of Lewis/Brønsted acid
(replacement of AlMe3 by TiCl4, BF3.OEt2, FeCl3, ZnCl2 or APTS)
did not increase the yield, nor the change of glycinate
contercation (Na+ replaced by Li+, Cs+ or Bu4N+, in order to
modify the solubility of the salt in acetone).
Scheme 2. Synthesis of oxazolidinone 9 with R = H.
We next tried to determine the rate of Ar-CO rotation. 1H NMR of
compound 10 at 217 K in THF-d8 (Figure 5) showed only two
sets of signals, two doublets for the acidic protons and two
singlets for the methyl groups with the same integration. This is
significant of a slow Ar-CO rotation (and not consistent with any
N-CO rotation, not observed): at low temperature, the two acidic
protons become different, one is close to the second phenyl
group and the other is on the opposite face; this is the same for
the methyl groups. Heating led to rapid Ar-CO rotation,
rendering the two acidic protons (or methyl groups) equivalent.
The coalescence occurred at 273 K for both signals. This led, in
the case of the methyl groups to a G≠ (the barrier to Ar-CO
rotation) of 53.7 kJ/mol.[48] Assuming constancy of G≠ with
temperature, we calculated the associated half-life for
racemization at -78 °C. The resulting value of 20 seconds was
not very encouraging. Despite this drawback and the moderate
yield of synthesis, we decided to pursue the optimization of
alkylation, as we already got a reasonable ee with this
oxazolidinone and as we did not succeeded in getting another
suitable chiral crystal.
Figure 3. Crystallographic structure of compound 9 (space group P21/c).
We then turned our attention back to the acetone derivative (R =
Me). We decided to use
phenylbenzoyl chloride. The synthesis was achieved in one step,
following the same procedure as before, using
a hindered aroyl chloride, o-
trimethylaluminium as a Lewis acid (Scheme 3). Fortunately, this
compound crystallized in a chiral space group P212121 (Figure 4).
The crystallographic structure showed that, as for
oxazolidinones 3 and 7, the aromatic moiety is oriented toward
the acidic proton.
Scheme 3. Synthesis of oxazolidinone 10 with R = Me.
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10[f]
11[f]
12[f]
3/10
0/10
0/75
27
33
11
79
84
55
THF/toluene
THF/toluene
THF/toluene
-78
-78
-78
297 K
278 K
276 K
273 K
272 K
271 K
269 K
267 K
217 K
[a] t1 is deprotonation time and t2 alkylation time [b] enantiomeric excesses
determined by chiral stationary-phase HPLC. [c] DME was replaced by 18-
crown-6. [d] conversion and ee determined by chiral stationary-phase HPLC
on the crude product. [e] toluene of KHMDS was removed and replaced by
THF. [f] reaction on fine powder arising from one large crystal.
Figure 5. VT-NMR of compound 10 in THF-d8.
From these preliminary experiments, several conclusions can be
drawn. The strategy is validated, but the configuration of the
enolate is not very stable (increasing the deprotonation time
induces a decrease of the ee, see entries 1-3). Reducing the
temperature did not improve the enantiomeric excess, but
instead decreased the yield, by reducing the solubility of the
crystals (entries 4-6). Change of solvent (either replacement of
THF by Et2O, or removal of toluene) was also not successful,
almost no reaction occurred in Et2O (entries 7-9).
Alkylation reactions
Our first attempts were made on small crystals, coming from
crystallization in diethylether. Every experiment was performed
on one crystal, weighting between 40 and 70 mg of either M or P
configuration and whose quality was not checked under
polarized light. Despite this drawback (that we were not aware of
at that time), we tried some alkylation reactions with allyl iodide.
The enantiomeric excesses are given without any mention of the
major enantiomer but both allylated enantiomers were clearly
distinguishable by chiral stationary-phase HPLC. We used the
previously optimized conditions for memory of chirality
reactions:[36] KHMDS in toluene as base and DME as additive.
We decided to add directly to ground crystals, at low
temperature, via cannula, a precooled solution of base, solvent
and additives. With that procedure, we should minimize the
racemization of compound 10 in solution, as it should be rapidly
deprotonated. The results are gathered in Table 3 (entries 1-9).
As we had some doubt about the crystals quality (the
enantiomeric excess of one alkylation may be better than
another, due to higher quality crystals), we decided to change
the crystallization procedure. Crystallization in diethyl ether led
to small crystals that were quality-checked under under
polarized light in a binocular microscope. This device is the most
appropriate tool for analyzing the quality and size of crystals:
normally, a high quality single crystal is well-shaped with visible
planar faces and induces a uniform extinction of polarized light,
showing that the crystal has no defects or twinning problems.
After this selection, a good crystal was fixed on a capillary and
was immersed in a saturated solution of compound 10 in diethyl
ether. After 2 or 3 weeks of gentle stirring, a large single crystal
weighting 2 g was obtained (Figure 6). After manual grinding,
the resulting fine white powder was used for allylation
optimization. In that case, the major alkylated enantiomer
obtained from one large ground crystal is always the same. The
results are also gathered in Table 3 (entries 10-12). Comparison
of entries 1 and 10 shows that this new method of crystallization
was more efficient. The enantiomeric excess was further
improved by adding directly a pre-cooled mixture of base,
solvent and electrophile to compound 10 (entry 11). Prolonged
reaction time was deleterious to both yield and enantiomeric
excess (entry 12): almost no starting material was present in the
crude product but dialkylated compound was observed. It means
that compound 11, already in solution, is deprotonated more
rapidly (and then either reprotonated or alkylated) than the
starting compound 10, still present as a solid suspension (even
though when only one equivalent of base is used). We then
moved to other electrophiles, which should be very reactive and
more hindered to avoid this issue.
Table 3. Alkylation of compound 10 with allyl iodide
[a]
Entry
t1/t2
Solvents
T
(°C)
Yield
(%)
ee[b] (%)
(min)
1
2
3
4
5
6
7
8
9
3/10
19
15
57
7
56
49
10
73
55
3[d]
-
THF/toluene
THF/toluene
THF/toluene
THF/toluene
THF/toluene
THF/toluene[c]
Et2O /toluene
Et2O /toluene
THF [e]
-78
-78
-78
-93
-93
-78
-78
-78
-78
10/10
30/10
10/10
30/10
3/10
10
3[c]
-
10/10
30/10
3/10
11
20
35
1
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13
14
15
PBM
PBM
PBM
(69)
(73)
48
(77)
(77)
96
30
0
1.2
1.2
1.2
DMPU (3)[h]
-
-
30
[a] unless specified, a pre-cooled solution of KHMDS (2 eq, 0.7 M in
toluene), electrophile 12 (5 eq), and additives in THF was added via
cannula at -78 °C to the powdered crystals of 10 (0.135 mmol). The mixture
was allowed to stir for 10 minutes at -78 °C. [b] M = manual grinding and
PBM = grinding with a planetary ball mill of crystals of compound 10. [c]
yields in brackets correspond to conversion, determined on the crude
product by HPLC. [d] enantiomeric excesses determined by chiral
stationary-phase HPLC. ee in brackets are determined on the crude
product. Racemic mixture for HPLC references were synthesized by
alkylation after previous dissolution of the crystals 10 at room temperature.
[e] reaction without toluene. [f] the reaction mixture was stirred 3 hours at -
78°C. [g] significant amount of dialkylated product was observed. [h] DMPU
was added just after the mixture of base, solvent and electrophile.
Figure 6. Picture of compound 10 crystallization.
We chose then m-benzyloxybenzyl iodide 12, because the
alkylated compound 13 could give access, after deprotection to
meta-tyrosine.[49] To ensure complete conversion, we used 2
equivalents of KHMDS. We kept the previously optimized
conditions, i.e. direct addition of a mixture of base, solvents and
electrophile onto powdered compound 10 and use of THF as
solvent. The results are presented in Table 4.
Our first trials were performed under crystals that were manually
reduced in fine powder. We got relatively high enantiomeric
excesses, we observed less dialkylation reaction but the
reaction was often not complete. At the end of some
experiments, we could see the white powder still in suspension.
Several attempts were made to improve the crystal solubility:
increase of THF quantity (compare entries 1 and 2), elimination
of toluene of the base (entry 3) and increase of the reaction time
(3 hours instead of 10 minutes, entry 6). None of these attempts
was successful. Several additives (and their amounts) were also
screened but the results are difficult to rationalize. DME seems
to be beneficial to the reaction (compare entries 4 and 5), but
TMEDA not (entry 11). The role of DMPU is not clear.
Unexpectedly, it seems to increase the enantiomeric excess but
not the yield (entries 7-10). We next tried to improve the
solubility of compound 10 by reducing it into a finer powder and
we ground the crystals with a planetary ball mill. In that case, we
got a high enantiomeric excess and a reasonable yield of
compound 13 (entry 14-15). No white powder was present
anymore at the end of the reaction. Addition of DMPU
decreased the enantiomeric excess (entries 12 and 13): it
probably enhanced the solubility of compound 10, but if it is too
rapidly in solution, without being deprotonated, Ar-CO rotation
occurs leading to racemization; addition of DMPU after the base
was less dramatic but was still abandoned. In the best
conditions, compound 13 was synthesized in 48% yield and 96%
ee. We tried to use this ball-mill technique in allylation reaction
but this was disappointing (compound 11, y = 59%, ee = 35%).
We wanted then to expand the scope of the reaction and used
the 2,4,6-tribromobenzyl iodide 14 as electrophile, as it can lead
to an biologically interesting analogue of phenylalanine.[50] We
observed that a reaction occurred between the base and the
electrophile. It was thus impossible to add them together to
compound 10. We proceed therefore to a sequential addition of
base and electrophile (Table 5). Our first trial gave access to the
expected compound 15 with high enantiomeric excess but low
yield (entry 1). Use of DMPU was deleterious to both yield and
enantiomeric excess (entry 2). On the contrary, grinding of the
crystals with a planetary ball mill really improved yield and
enantiomeric excess (entries 3-6). In that case, use of 30
equivalents of DME or higher volume of THF decreased the
Table 4. Alkylation of compound 10 with m-benzyloxybenzyl iodide[a]
Entry
Grin-
n1 eq of
V
additive
Yield[c] (%) ee[d]
(%)
ding[b] DME
(mL) (n2 eq)
1
M
(42)
(88)
2.1
2.1
2.1
30
0
1
-
2
M
45(60)
(65)
72(72)
(20)
5
-
5[e]
1.2
1.2
1
-
3
M
4
M
(58)
(88)
-
5
M
(42)
(83)
-
6[f]
7
M
64(99)[g]
24(43)
26
73(74)
96(97)
90
2.1
30
0
-
M
1.2
1.2
5
DMPU (3)
DMPU (3)
DMPU (3)
DMPU (10)
TMEDA (30)
DMPU (3)
8
M
9
M
41(60)
(59)
88(72)
(60)
2.1
2.1
0
10
11
12
M
5
M
(22)
(65)
1.2
1.2
PMB
(62)
(23)
30
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enantiomeric excess. Reducing the deprotonation time to the
practical minimum (addition via cannula of the base and the
solvents) lead to compound 15 with 70% yield and 90%
enantiomeric excess (entry 4). Enantiopure compound 15 was
obtained after recrystallization in a mixture of THF and pentane
(yield of recrystallization = 55%). Crystallographic structure of
compound 15 (Figure 7) allowed us to determine the absolute
configuration of this sample, as heavy bromine atoms were
present on the molecule. It was then deduced that the R
Piperonyl iodide was also used as the corresponding alkylated
compound could give access to L-DOPA. Alkylation results are
summarized in Table 6. As before, grinding the crystal with a
planetary ball mill improved the yield. In that case, increasing the
THF volume was beneficial (compare entries 1 and 2 or 4 and 5).
In the best conditions, alkylated compound 17 was obtained in
57% yield and 87% enantiomeric excess.
enantiomer possesses longer retention time than the
enantiomer.
S
Table 6. Alkylation of compound 10 with piperonyl iodide[a]
Table 5. Alkylation of compound 10 with 2,4,6-tribromobenzyl iodide[a]
[c]
Entry
Grin-
n eq of
DME
V (mL)
t1/t2
Yield[d] ee[e]
Entry Grinding[b]
V (mL)
t (min)
10
Yield[c] (%) ee[d] (%)
ding[b]
(min)
(%)
(%)
1
2
3
4
5
M
(21)
(37)
(77)
50(77)
57
(94)
(93)
(45)
83(83)
87
1.2
5
1
M
0.5/9.5
0.5/9.5
0.5/9.5
0.33/9.67
0.5/9.5
0.5/9.5
18
82
2.1
2.1
2.1
2.1
30
1.2
1.2
1.2
1.2
1.2
5
M
10
2[f]
3
M
25
28
M
30
5
PBM
PBM
PBM
PBM
68
80
PBM
PBM
10
1.2
5
4
70
90
10
5
(90)
(98)
(50)
(30)
[a] unless specified, a pre-cooled solution of KHMDS (2 eq, 0.7 M in
toluene), electrophile 16 (5 eq), and additives in THF was added via
cannula at -78 °C to the powdered crystals of 10 (0.135 mmol). The
mixture was allowed to stir for t minutes at -78 °C. [b] M = manual
grinding and PBM = grinding with a planetary ball mill of crystals of
compound 10. [c] yields in brackets correspond to conversion,
determined on the crude product by HPLC. [d] enantiomeric excesses
determined by chiral stationary-phase HPLC. ee in brackets are
determined on the crude product. Racemic mixture for HPLC references
were synthesized by alkylation after previous dissolution of the crystals
10 at room temperature.
6
30
[a] unless specified, a pre-cooled solution of KHMDS (2 equiv, 0.7 M in
toluene), and additive in THF was added via cannula at -78 °C to the
powdered crystals of 10 (0.135 mmol). After t1 minutes, electrophile 14 (5
equiv) was added and the mixture allowed to stir for t2 minutes at -78 °C. [b]
M = manual grinding and PBM = grinding with a planetary ball mill of
crystals of compound 10. [c] t1 is deprotonation time and t2 alkylation time
[d] yields in brackets correspond to conversion, determined on the crude
product by HPLC. [e] enantiomeric excesses determined by chiral
stationary-phase HPLC. ee in brackets are determined on the crude
product. Racemic mixture for HPLC references were synthesized by
alkylation after previous dissolution of the crystals 10 at room temperature.
[f] 3 equivalents of DMPU were also added with base and solvents.
Applying some optimized conditions (30 equivalents of DME,
crystal ground by a planetary ball mill), the other following
electrophiles were also tested: 1-(iodomethyl)naphthalene, 1-
(bromomethyl)naphthalene,
tert-butylbromoacetate,
tert-
butyliodoacetate, o-phenylbenzyl iodide, o-trifluoromethylbenzyl
iodide, o-methoxybenzyl iodide. The enantiomeric excesses
were rather disappointing, ranging from 13% to 60% but
sometimes with low conversion.[51] The best results were
obtained with o-methoxybenzyl iodide, the alkylated compound
was synthesized in 80% yield and 58% enantiomeric excess
(scheme 4).
Figure 7. Crystallographic structure of compound 15.
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Scheme 4. Alkylation of compound 10 with 2-methoxybenzyl iodide.
Deprotection

The next step we had to investigate was deprotection to get the
final tertiary amino acids. We had to be more cautious than in
our previous work on asymmetric synthesis of quaternary -
amino acids (by memory of chirality) because now racemization
can occur during this step. For the optimization phase, we used
compound arising from various trials with different enantiomeric
excesses. As we have faced some problems of formation of
fluorenone during the oxazolidinone synthesis, our first idea was
to benefit from this reaction and we tried to induce the reaction
by activating the amide. Several attempts were made in this
direction: reaction with BF3.OEt2, or Tf2O, or POCl3. In every
case, we observed either starting material, or degradation. We
tested also acidic hydrolysis (in refluxing HCl 6M) on compounds
13 and 15 but it led to degradation. We tried then to reduce the
amide into imine: with borane, no reaction occurred and with
Schwartz reagent,[52,53] we observed reduction of the lactone
moiety into lactol. We then decided to proceed sequentially.
Hydrolysis of the oxazolidinone ring was achieved in basic
conditions on compounds 13 and 15 (NaOH, THF/H2O, reflux,
24h). The corresponding carboxylic acid was obtained in
quantitative yield from compound 13 but slight degradation
occurred on compound 15, leading to various yields (75-90%).
We improved these conditions for compound 15 by using the
Scheme 5. Final steps: synthesis of enantiopure aminoester 21.
Sorting of the crystals
As synthetic chemists, we felt concerned about the selection of
the configuration of the final compound. Knowing that in the
initial crystallization, small crystals of both configuration (M or P)
are present, the problem consisted in the choice of the desired
crystal to get either the R or S final amino ester. We tried to sort
the crystal manually like Pasteur but we did not observe any
notable difference. Hopefully sorting the oriented crystals under
polarized light lead to two types of crystals (this was achieved on
small crystals, the large ones being too thick for the light to get
through): the positive ones, which induced light extinction when
turned right and the negative ones, which induced light
extinction when turned left. Alkylation under optimized conditions
was performed three times on crystals of each sign (twice on
small crystals and once on a large crystal after crystal growth)
and lead to both enantiomers of compound 15. HPLC analyses
of compounds 15 on a chiral stationary phase showed that the
positive crystals gave access to the R enantiomer (longer
retention time, as determined by crystallographic structure) and
the negative ones to the S enantiomer. We were thus able to
sort the crystal to get the desired alkylated compound.
Evans auxiliary cleavage conditions.[54] In fact, use of
2
equivalents of lithium hydroxide and 6 equivalents of hydrogen
peroxide gave quantitatively access to the expected opened
compound without racemization. Application of several
conditions (Tf2O, or refluxing HCl 6M, refluxing HBr 47% or
Schwartz reagent) led either to starting material or degradation.
We chose then to esterify the carboxylic acid in mild conditions.
Use of trimethylsilyldiazomethane and methanol in THF led
quantitatively to compound 20 without racemization. The final
step to achieve was the removal of the aromatic amide. No
reaction was observed with phosphoryl chloride, and
degradation occurred with triflic anhydride, 2F-pyridine and
triethylsilane (formation of an oxazole with the amide was
observed).[55] Use of Schwartz reagent followed by acidic
hydrolysis of the imine intermediate gave the aminoester 21
without racemization. When this sequence was repeated on the
enantiopure compound (S)-15, the final aminoester was
obtained in enantiopure form with 43% yield (scheme 5).
Reduction to amino alcohol
We also wanted to have access to amino alcohol. This was
achieved in 3 steps: a) oxazolidinone basic hydrolysis b)
reduction of the carboxylic acid by using LiAlH4 and c)
diphenylsilane with titanium tetraisopropoxide reduction[56,57] to
get the final amino alcohol. This sequence was performed on
compound 13, with 94% ee (with probably S configuration as the
starting crystal was a negative one) and led to the corresponding
alcohol 23 with almost no racemization (ee = 90%, determined
after Boc protection) (scheme 6).
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Spectra calculations
Calculations were performed on the enantiomer A of absolute
configuration (aS). The geometry optimizations, vibrational
frequencies, IR absorption and VCD intensities were calculated
with Density Functional Theory (DFT).[59]
IR and VCD spectra measurements
IR and VCD spectra measured for 10a and 10b and calculated
for A are given in figure 11. The measured and calculated IR
absorption spectra are in good agreement except for bands 1 to
4 (figure 11). Indeed, only singlet 1 (1800 cm-1) and 3 (1650 cm-
1) appear on the calculated spectra whereas doublets (1,2) and
(3,4) are measured. The vibrational modes related to these two
bands are stretching C=O of respectively the ester (1) and amide
(3) moieties. Several hypotheses can explain the presence of
these doublets. However a spatial intermolecular coupling
between C=O vibrational modes seems to be the most reliable
explanation. Indeed, this kind of coupling is related to an intense
couplet on the VCD spectrum as measured for bands (3,4). For
bands (1,2), none intense couplet is observed due to the cutting
of the spectrum at 1800 cm-1. It is worth noting that the coupling
between two or more oscillators is strongly dependent of their
relative position. Short contacts analysis in the unit cell of the
crystallographic structure of 10a (or 10b) shows that the
proximity and the relative orientations of the molecules in the
crystal are consistent with this hypothesis. In order to validate it,
from the crystallographic structure, we have retained two models
AA and AB with respectively two and six molecules. Their
structures were thus optimized (Figure 10) and their IR and VCD
spectra were calculated (Figure 9). The geometries optimized
using B3LYP-GD3/6-311G(d,p) level are close to the geometry
in the crystal. The IR absorption spectra of AA and AB are in
better agreement with the one measured. For AA, the doublets
(1,2) and (3,4) appear now on the calculated spectra. The
vibrational mode related to the (1,2) doublet is the stretching
C=O of the ester group of alternatively the first, and the second
molecule. For the doublet (3,4) of the spectrum of AA, the C=O
bonds of the two amide group are stretched together in phase
(3) or in opposite phase (4). Despite a better agreement with
experiment, this model seems to be too simple. Indeed, analysis
of the stretching C=O of the ester groups in AB model shows
that in addition to vibrational modes C=O localized on one
molecule, there are also vibrational modes where the C=O
bonds are stretched together as describe previously for couplet
(3,4). Moreover with AB, the relative positions of the two
doublets (1,2) and (3,4) are in better agreement with
measurement. This indicates that the model AB is able to
correctly describe the structure, and also means that in the pellet,
the crystal structure seems to be preserved. This has also
consequences on the VCD spectra. Indeed, model AA is not
able to correctly modelize the (3,4) couplet whereas model AB is
closer to the measurements (figure 9). Despite these two models
confirm clearly the spatial coupling between carbonyls, more
sophisticated models are required to model correctly the
doublets (1,2) and (3,4). More interesting are the bands below
1500 cm-1. Indeed, in this area, calculated bands don't depend of
the retained model A, AA or AB. Particularly for the three
Scheme 6. Access to amino alcohol 23.
Stereoselectivity rationalization
In order to rationalize the results, we wanted to determine the
absolute configuration of oxazolidinone 10 in an enantiopure
crystal. As no “heavy” atom was present in compound 10, we
planned to perform Vibrational Circular Dichroism (VCD). We
had in our hands two crystals of opposite absolute configuration
(leading to opposite alkylated enantiomers, as seen on HPLC
chromatograms). The absolute configuration of enantiomers 10a
(positive crystal, leading to
R absolute configuration for
compound 15, as determined by crystallographic structure) and
10b (negative crystal, leading to S absolute configuration for
compound 15, as seen on HPLC chromatogram) was
established by comparison of the measured spectra with those
calculated for the enantiomer
A (Figure 8) of absolute
configuration (aS). In order to check that the way used for
making KBr pellet (see supporting information) of 10a and 10b
preserve the X-ray geometry and totally exclude the participation
of other conformations to the average spectra, we explored the
conformational space of A. The calculations[58] show clearly that
only X-ray conformation is significantly populated (see
supporting information).
Figure 8. Conformer A with (aS) absolute configuration.
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models, bands 9 and 13 are related to vibrational modes
localized on one molecule, i.e without intermolecular spatial
coupling. Those bands are reliable to establish the absolute
configuration of enantiomer 10a is (aS) and consequently (aR)
for the enantiomer 10b.
measurements preserves its crystallographic structure. Indeed, it
is necessary to calculate IR absorption and VCD spectra for the
crystallographic structure with six molecules instead of one in
order to have a good agreement with measurements. The
conformational study performed on enantiomer A showed that
only one conformation is significantly populated. This
conformation has geometry similar to that of the molecule in the
crystal.
As the crystallographic structure of compound 15 gave access to
the absolute configuration of the alkylated compound and the
VCD allowed the determination of the absolute configuration of
the starting material crystal, we were able to conclude that
alkylation occurred opposite to the aromatic substituent
(Scheme 7). Overlay of the crystallographic structures of
compounds 10 and 15 supports this hypothesis as they are
really similar (Figure 11).
Figure 9. IR absorption and VCD spectra measured for 10a (green) and 10b
(red) and calculated for A (orange), AA (purple) and AB (blue) using B3LYP-
GD3/6-311G(d,p) theoretical level.
Scheme 7. Stereoselectivity explanation.
AA
AB
Figure 10. Geometries of the structures AA and AB with respectively 2 and 6
molecules.
Figure 11. Overlay of crystallographic structures of compounds 10 (red) and
15 (blue). Hydrogens have been omitted for clarity.
In conclusion, combination of absorption and VCD measurement
with DFT calculations allowed us to elucidate unambiguously the
absolute configuration of the two enantiomers: 10a possesses
the (aS)-configuration and 10b possesses the (aR)-configuration.
In addition, this study showed that the preparation of the sample
(KBr pellet from crystals of each enantiomer) before the
Conclusions
We have demonstrated that we were able to perform an
absolute asymmetric synthesis of tertiary amino acids. We thus
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We thank the Marie Curie program for a IIF fellowship (post-
doctoral fellowship to B.V., grant PIIF-GA-2011-300491) and the
ANR (Agence Nationale de la Recherche; ANR grant n°ANR-08-
JCJC0099, doctoral grant to T.T.M.) for financial support. The
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Keywords: Amino acid • Asymmetric synthesis • VCD • Crystal •
Frozen chirality
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Entry for the Table of Contents
FULL PAPER
Frozen chirality, an efficient
Dr. T.T. Mai, Dr. B. Viswambharan, D.
Gori, Dr. R. Guillot, Dr. J.-V. Naubron,
Prof. Dr. C. Kouklovsky, Dr. V. Alezra*
strategy for absolute asymmetric
synthesis? We describe here an
efficient and rationalized absolute
asymmetric synthesis of tertiary -
amino acids, based on frozen chirality:
a chiral conformation of an achiral
compound is frozen in a crystal. -
Amino ester or amino alcool are thus
synthesized in high ee.
Page No. – Page No.
Frozen Chirality of Tertiary Aromatic
Amides: Access to Enantioenriched
Tertiary -Amino acid or Amino-
Alcohol without any Chiral Reagent.
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