Substrate control in enantioselective and diastereoselective aldol reaction by memory of chirality: A rapid access to enantiopure β-hydroxy quaternary α-amino acids

Article abstract of DOI:10.1021/ol403523e

An asymmetric aldol reaction by memory of chirality is reported with a substrate control of stereoselectivity by aldehyde and rationalized. Starting from l-alanine, several diastereopure and enantioenriched β-hydroxy quaternary α-amino acids have been obtained in three steps. The initial chirality of l-alanine is memorized through the dynamic axial chirality of tertiary aromatic amide.

Full text of DOI:10.1021/ol403523e

Letter
pubs.acs.org/OrgLett
Substrate Control in Enantioselective and Diastereoselective Aldol
Reaction by Memory of Chirality: A Rapid Access to Enantiopure
β‑Hydroxy Quaternary α‑Amino Acids
Baby Viswambharan,† Didier Gori, Regis Guillot, Cyrille Kouklovsky, and Valerie Alezra*
́
́
́ ́ ̂
Institut de Chimie Moleculaire et des Materiaux d'Orsay (ICMMO-UMR 8182), Univ. Paris-Sud, CNRS, Bat 410, Orsay F-91405
France
S
* Supporting Information
ABSTRACT: An asymmetric aldol reaction by memory of
chirality is reported with a substrate control of stereoselectivity
by aldehyde and rationalized. Starting from L-alanine, several
diastereopure and enantioenriched β-hydroxy quaternary α-
amino acids have been obtained in three steps. The initial
chirality of L-alanine is memorized through the dynamic axial
chirality of tertiary aromatic amide.
molecular aldol reaction but with low stereoselectivities, and
Kawabata’s intermolecular aldol reaction led to oxazolidinone
formation with inversion of configuration in high yields and
stereoselectivities.8 However, these oxazolidinones were not
hydrolyzed. In our group, we have developed a three-step
MOC synthesis of quaternary α-amino acids based on the
dynamic axial chirality of tertiary aromatic amides.9 We have
performed alkylation of oxazolidinones derived from natural
amino acids and got quaternary α-amino acids in high yields
and enantiomeric excesses.10 We describe herein the extension
of this methodology to the aldol reaction, which is a greater
challenge as a second asymmetric center is formed (Scheme 1).
We chose L-alanine as the starting amino acid as our previous
studies showed that the corresponding enolate was more
configurationally stable, and this could be used later in the total
synthesis of sphingofungin F, a bioactive molecule known to
have potent antifungal activity and also inhibitory activity
against serine palmitoyl transferaes (SPT).2b We synthesized
uaternary α-amino acids are a large class of compounds
Q that include many biologically active members and thus
have attracted much attention of research groups.1 Among the
quaternary α-amino acids, β-hydroxy amino acids occupy a
special place as they are present in several interesting natural
active compounds such as lactacystin, kaitocephalin, or
sphingofungin, etc. (Figure 1).2
Figure 1. Structures of biologically active natural β-hydroxy quaternary
α-amino acids.
Scheme 1. Previous Work on Memory of Chirality and
Application to Aldol Reaction
The aldol reaction seems to be a straightforward access to the
quaternary β-hydroxy amino acids, and classical approaches for
their stereoselective synthesis have been described.3 Methods
using only the initial chirality of a starting α-amino acids such as
the self-regeneration of stereocenters developed by Seebach4 or
the memory of chirality (MOC)5 have also been employed. A
reaction proceeding with memory of chirality has been defined
by Carlier as “a formal substitution at a sp3 stereogenic center
that proceeds stereospecifically, even though the reaction
proceeds by trigonalization of that center, and despite the fact
that no other permanently chiral elements are present in the
system”. A few examples of aldol reactions have been described
so far with the MOC principle, the earliest reported reactions
being intramolecular.6 Recently, Ghorai7 succeeded in inter-
Received: December 5, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol403523e | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
oxazolidinone 1 as previously described and then tried to
optimize the aldol reaction conditions by using benzaldehyde.
Oxazolidinone 1 exists as four conformers (P,cis:M,cis:P,-
trans:M,trans) in solution at −78 °C with P,cis being major.
The initial experiment, the addition of KHMDS in THF and
DME to a solution of 1 in THF under argon at −78 °C and
quenching by acetic acid, was disappointing as we observed
only a trace of 2a,b. The yields were improved by replacing
acetic acid with NH4Cl, and then removed the acidic residues
by washing with 5% NaHCO3 solution to avoid the acidic
cleavage of the oxazolidinone ring. We tried various conditions
to further improve the yield, ee and dr (Table 1).
increased the amount of solvent to avoid freezing, but dilution
of the reaction led to decrease of the dr). Therefore, a direct
addition of commercially available uncooled KHMDS solution
via syringe to the mixture of 1 and benzaldehyde simplified the
condition. This allowed us to perform a more concentrated
reaction as dilution led to lowering of dr. Addition of the
aldehyde after deprotonation was deleterious for the enantio-
meric excess (Table 1, entry 6), and this is probably significant
of the enolate racemization. Besides, a rapid addition of the
base led to a decrease of stereoselectivity (Table 1, entry 7)
probably because a rapid addition of an uncooled base, coupled
with an exothermic deprotonation reaction, should induce
warming and thereby enolate racemization. Slow addition of an
uncooled base improved the enantio- and diastereoselectivity
(Table 1, entries 7 and 8). Going from 10 to 12 min of reaction
decreased the dr and improved the yield (Table 1, entries 8 and
9). This is perhaps due to the reaction of the minor conformers.
We also observed a change of enantio- and diastereoselectivity
depending on the temperature at which the benzaldehyde and
the oxazolidinone were mixed (Table 1, entries 9 and 10). To
Table 1. Optimization of Aldol Reaction of Oxazolidinone 1
a
with Benzaldehyde
1
understand this, we performed two H NMR experiments.
Premixing oxazolidinone 1 and benzaldehyde (5 equiv) in
THF-d8 at RT and recording the 1H NMR spectrum at −78 °C
showed two aldehyde peaks, probably due to the presence of
free and complexed aldehyde. Moreover, we observed several
conformational changes in the oxazolidinone part (more visible
for the acidic proton and for the dimethyl group). The
conformational change could have happened because of the
π−π interaction between the naphthoyl group and the
benzaldehyde in a complexed form. Whereas when benzalde-
hyde is mixed with oxazolidinone 1 at −78 °C and the spectra
are recorded at the same temperature, we did not observe any
such effects (see Supporting Information). We tried other
solvents (ether or DME) and addition of a Lewis acid or other
bases (KHMDS in toluene or LiHMDS gave no product at all)
but observed no improvement. Thus the best conditions are the
ones of entry 8.
c
d
vol
t
ee (%)
yield
b
entry
n
(mL) additive (min)
dr
2a/2b
(%)
ef
,
1
1.0
1.5
2.0
2.0
2.0
2.0
1.5
1.5
1.5
1.5
0.35
1.5
DME
DME
DME
10
10
10
10
10
10
10
10
12
12
83:17
86:14
83:17
72:28
75:25
82:18
66:34
89:11
75:25
80:20
83/79
84/74
79/73
83/82
84/79
34/18
68/46
83/75
83/79
72/64
71
85
90
57
80
78
80
78
82
85
ef
,
2
3
4
5
6
ef
,
1.7
e g
−
1.7
e h
−
1.7
e gi
− ,
1.7
jk
7 ,
0.52
0.52
0.52
0.52
k m
−
8
9
kl
,
ln
10 ,
a
General procedures: To a stirred solution of oxazolidinone 1 (0.35
mmol) in THF (1.2 mL) at −78 °C was added benzaldehyde (5
equiv) just before adding a solution of KHMDS (n equiv) in THF (V
mL) dropwise (over 2 min), and the mixture was stirred for t min at
−78 °C. Ratio 2a/2b determined by chiral stationary-phase HPLC on
the crude product. Ee of 2a/2b determined by chiral stationary-phase
HPLC after purification. Combined yield of 2a and 2b. Addition of a
precooled KHMDS solution via canula. Toluene was removed from
the commercially available solution of KHMDS and replaced by THF.
Washed with NaHCO3 1% solution. Benzaldehyde distilled from
CaH2 just before use. Identical to general procedure, except that
KHMDS is added first and benzaldehyde is then added after 1.5 min.
Direct and rapid addition of a room temperature KHMDS solution.
Commercially available 1 M solution of KHMDS in THF was used.
b
We next performed the MOC aldol reactions successfully
with various aromatic or heteroaromatic aldehydes and
cinnamaldehyde. Two aliphatic aldehydes (isobutyraldehyde
and pivalaldehyde) were unsuccessfully tested. Moreover, a
reactive ketone, 1-Me-isatin, also reacted well (Table 2, entry
15), allowing the generation of two contiguous quaternary
centers, but the diketone benzyl was found unreactive. For each
aldehyde, we separately optimized the reaction time to get the
best results (for ee, dr, and yields), other conditions being kept
constant (Table 2). From these results, the ee of the major
diastereomer is often superior to 80% and is up to 94% (Table
2, entry 13). Fortunately, all the diastereomers were separable
by chromatography. In most of the cases, the products
coexisted as conformers, and it is confirmed by the variable-
c
d
e
f
g
h
i
j
k
l
Direct and slow addition of a room temperature KHMDS solution.
m
n
Relative configuration of dia a determined by X-ray. Benzaldehyde
was added to 1 in THF at RT and cooled to −78 °C.
The addition of a precooled solution of base in THF and
DME (2 equiv, diluted to avoid freezing at −78 °C) to a
solution of oxazolidinone and electrophile (5 equiv) in THF
gave the expected aldol 2a and 2b in 71% combined yield, with
a dr of 83:17 (separable diastereomers) and ee of 83 and 79%,
respectively (Table 1, entry 1); 1.5 equiv of KHMDS was
sufficient to ensure good conversion (Table 1, entries 1−3).
DME, as an additive, was excluded from the reaction for
simplification (Table 1, entries 3 and 4). The quality of
benzaldehyde was essential for a better yield (Table 1, entries 4
and 5). Precooling of the base solution did not considerably
improve the stereoselectivity of the reaction (we subsequently
1
temperature H NMR experiments (see Supporting Informa-
tion).
On the other hand, the dr is highly dependent on the
aldehyde; from o-Br (a major) to o-F (b major), there is a
diastereo switching, and for furan aldehyde, the diastereo-
selectivity is completely opposite (Table 2, entries 6, 11, and
12). Thiophene aldehyde lies in the borderline. 1-Methyl-isatin
showed the same trend at lower reaction concentration (Table
2, entry 15). As we found for benzaldehyde (Table 1), both
dilution and reversal of mode of addition of electrophile led to
decrease and reversal of dr (Table 2, entry 16).
B
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Organic Letters
Letter
Table 2. Aldol Reaction of Oxazolidinone 1 with Aldehydes or 1-Me-isatin
a
b
entry
Ar-
n (s)
t (min)
comp
dr
ee (%)
yield (%)
c
c
1
2
o-Me-C6H4-CHO
o-Me-C6H4-CHO
p-OMe-C6H4-CH
m-Br-C6H4-CHO
m-Br-C6H4-CHO
o-Br-C6H4-CHO
p-Me-C6H4-CHO
p-Me-C6H4-CHO
3-pyridine-CHO
2-thiophene-CHO
o-F-C6H4-CHO
2-furan-CHO
60
12
12
12
15
15
12.5
512
12
12
12
15
8
3
3
4
>98:2
>98:2
78/−
82 /−
48
48
67
90
72
81
56
73
71
68
56
68
75
99
d
120
120
150
240
95
c
3
88:12
73/56
79/65
89/68
75/90
e
c
4
5
92:8
c
5
5
87:13
f
g
6
6
93:7
80:20
78:22
c
c
d
7
95
7
7
8
9
78 /73
8
120
105
105
120
105
105
90
82/78
85/92
75/71
88/78
g
g
c
9
79:21
50:50
10
11
12
13
14
15
16
e
10
30:70
15:85
10:90
83:17
42:58
68:32
h
c
c
c
c
c
i
11
83/93
j
2-furan-CHO
12
12
12
8
11
12
13
13
77/94
Ph-CHCH-CHO
87/65
53/87
58/78
k
1-Me-isatin
120
120
49
l
1-Me-isatin
80
a
b
c
Ee of diastereomers a/b determined by chiral stationary-phase HPLC after purification. Combined yield of both diastereomers. Dr a/b (a being
d
the less polar) determined by 1HNMR on the crude product. Recrystallization allowed improvement of ee for 3a: ee >99%, yield = 66%; for 7a: ee
= 93%, yield = 70%. Relative configuration of dia a determined by X-ray. Absolute configuration of dia a determined by X-ray. Dr a/b (a being the
e
f
g
h
i
less polar) determined by chiral stationary-phase HPLC on the crude product. Relative configuration of dia b determined by X-ray. Ee observed for
the crude product: 86/96.11 Ee observed for the crude product: 91/95. 1-Me-isatin was sparingly soluble at −78 °C. 1-Me-isatin (3 equiv) in 2.2
j
k
l
mL of THF was added after KHMDS.
Several aldol compounds were recrystallized to determine
relative and absolute configurations by X-ray structures.
Compounds 2a and 5a crystallized as racemic leading to the
determination of the relative configuration (either RR or SS)
and to an improvement of the ee in the mother liquor (mother
liquor: 2a (yield = 90%; ee = 98%); 5a (yield = 78%; ee =
95%)). Compounds 6a (yield = 74%; ee >99%), 10a (yield =
80%; ee >99%), and 11b (yield = 60%; ee >99%) were
obtained as enantiopure by recrystallization. The X-ray
structures (Figure 2) showed that compounds 2a, 5a, 6a, and
10a possess the same relative configuration, and for 6a (which
possesses a bromine atom), the configuration of the first
asymmetric center is retained (R), as observed for alkylation
reactions. Moreover, the relative configuration of 11b was
opposite to the previous one. Considering the resemblance of
the 1H NMR spectra for each diastereomer in all aldol
products, we extended the preceding stereochemistry to all
compounds (including for compound 13).
The observed stereochemistry can be explained by a
Zimmerman−Traxler transition state (Figure 3). As already
Figure 3. Explanation for the observed stereoselectivity: the favored
transition states TS A leading to diastereomer a and TS B leading to
diastereomer b are presented.
rationalized for alkylation,10 the initial orientation of the
naphthoyl group is retained during enolate formation and
induces an electrophile approach through the opposite face
(leading to the observed retention of configuration for the α-
carbon). In the chairlike Zimmerman−Traxler transition state
TS A, due to the presence of the five-membered ring and the
dimethyl group in it, the C−N bond is pseudoequatorial,
Figure 2. X-ray structures of compounds 2a and 5a (racemic, major
enantiomer shown), 6a, 10a, and 11b (enantiopure).
C
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Organic Letters
Letter
Present Address
†Secondary address: UniverSud Paris-Les Algorithmes, Bat
ment Euripide 91194 Saint-Aubin, Cedex France.
whereas the methyl group is pseudoaxial. The aromatic ring of
the approaching aldehyde can orient in pseudoequatorial
position, leading to the observed major diastereomer a.
This pseudoequatorial position (TS A) of the aromatic ring
is even more favored when the aromatic ring is hindered such
as with the o-Me-phenyl and o-Br-phenyl groups and allowed
an almost perfect diastereoselectivity (Table 2, entries 1 and 6).
Surprisingly, we observed a reversal of diastereoselectivity when
the phenyl group is substituted at the ortho position with
fluorine atom (10b is major, Table 2, entry 11). This was also
the case when furan aldehyde was used as an electrophile
(Table 2, entries 12 and 13). When a donor atom is present at
the aromatic ring, there could be an extra anchoring interaction
between the pseudoaxial aromatic ring and the metal, thereby
stabilizing the TS B, resulting in the major formation of
diastereomer b. For 3-pyridine aldehyde, the coordinating atom
is away from the coordinating position. For thiophene
aldehyde, both TS A and TS B may be equally possible. TS
B must be favored for the o-fluorobenzaldehyde but not for the
o-bromobenzaldehyde (6a is major, entry 6), as o-Br is too
bulky compared to o-F. To our knowledge, this type of
diastereocontrol by the aldehyde has not been observed so far
for aldol reactions with a chairlike transition state, but a similar
case has been described for allylation reaction of aldehydes.12
Four compounds were hydrolyzed in one step and led to β-
hydroxy quaternary α-amino acids as hydrochloride in good to
excellent yields (Scheme 2).
̂
i-
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research leading to these results has received funding from
the European Union Seventh Framework Programme (FP7/
2007-2013) under Grant Agreement No. 246556 (RBUCE-UP
postdoctoral fellowship to B.V.). We thank also the ANR
(Agence Nationale de la Recherche; ANR Grant No. ANR-08-
JCJC0099) for financial support.
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We have presented here an efficient synthesis of β-hydroxy
quaternary α-amino acids, using only the initial chirality of the
starting α-amino acid. This is the first example of a MOC aldol
reaction that allows the synthesis of the final compounds in
three steps, and several β-hydroxy quaternary α-amino acids
have been obtained in diastereopure and enantioenriched form.
We have moreover highlighted a surprising substrate control of
the stereoselectivity from the aldehyde side which, to our
knowledge, has not been so far described in the aldol reaction.
An explanation of the observed stereoselectivity has been
proposed. Extension of this reaction to other amino acids is
currently under investigation.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Crystallographic data of compounds 2a, 5a, 6a, 10a, and 11b
and experimental details and characterization of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: valerie.alezra@u-psud.fr.
D
dx.doi.org/10.1021/ol403523e | Org. Lett. XXXX, XXX, XXX−XXX