Oxidative coupling of enolates using memory of chirality: An original enantioselective synthesis of quaternary α-amino acid derivatives

Article abstract of DOI:10.1039/c8cc06864j

We describe here the first enantioselective oxidative heterocoupling of enolates. Our strategy relies on the memory of chirality concept and allows the stereocontrolled formation of quaternary centres on α-amino acid derivatives with an enantiomeric excess of up to 94%.

Full text of DOI:10.1039/c8cc06864j

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Oxidative coupling of enolates using memory
of chirality: an original enantioselective synthesis
of quaternary a-amino acid derivatives†
Cite this: Chem. Commun., 2018,
4, 12742
5
Received 23rd August 2018,
Accepted 18th October 2018
Antonin Mambrini,
Valerie Alezra
Didier Gori, Regis Guillot,
Cyrille Kouklovsky
and
´
*
´
DOI: 10.1039/c8cc06864j
rsc.li/chemcomm
We describe here the first enantioselective oxidative heterocoupling of has been involved for many years in the development of
enolates. Our strategy relies on the memory of chirality concept and asymmetric syntheses of quaternary a-amino acids based on
allows the stereocontrolled formation of quaternary centres on the MOC principle. We have thus described efficient intermole-
a-amino acid derivatives with an enantiomeric excess of up to 94%.
cular alkylation or aldol reactions of enolates by memorizing
the initial central chirality of a natural tertiary a-amino acid in the
1
,2
37–40
Oxidative coupling of enolates is a very powerful synthetic axial chirality of tertiary aromatic amides (Scheme 1).
We wanted
method as it enables direct access to 1,4-dicarbonyl compounds, to extend our strategy to radical reactions in order to enlarge its
which are not easy to make as their synthesis requires functional scope, our aim being to achieve oxidation of the intermediate
group umpolung strategies. In recent years, extensive research enolate into a stabilized captodative radical. In this paper, we report
3
works have provided several methods for efficient intra and our efforts towards enantioselective oxidative heterocoupling of
4
,5
intermolecular oxidative coupling. However, most of them enolates using memory of chirality and consequently describe the
are racemic or rely on preexisting stereogenic centers in the first enantioselective version of this reaction.
enolate precursor as a chiral inducer (diastereoselective oxida-
We used oxazolidinone 1 derived from L-alanine to screen
6
–10
tive coupling).
To develop an enantioselective version of this oxidants. We chose acetophenone as the other partner since
reaction, application of traditional means such as enantio- deprotonation can occur only on one side and because the
selective catalysis or use of enantiopure stoichiometric reagents electronic character of the enolate is easily tunable by changing
seems difficult. There is only one example of enantioselective the substituents of the aromatic ring. The results for oxidant
oxidative homocoupling of a titanium enolate with a chiral screening are reported in Table 1.
ligand but the meso compound is the major product and the
The most promising results were obtained with Cu(2-ethyl-
hexanoate) as an oxidant (entry 1). Several byproducts were
1
1,12
enantiomeric excess of the chiral diastereomer is only 76%.
2
1
3–15
On the contrary, the memory of chirality (MOC)
strategy
appears to be promising in this context. Indeed, in an MOC
reaction, the initial chirality of the starting material is retained
during the reaction in the global chiral conformation of the
molecule, which should be the case for the generated radical.
This strategy has mostly been applied to carbanion inter-
1
6–22
23,24
25–34
mediates
but also to carbocations
or radicals.
In radical reactions there are only two examples of inter-
molecular MOC reactions: one recombines 2 radicals in close
3
5
36
3
vicinity, and one uses arene–Cr(CO) complexes. Our group
Facult ´e des Sciences d’Orsay, Univ. Paris-Sud, Laboratoire de M ´e thodologie,
Synth `e se et Mol ´e cules Th ´e rapeutiques, ICMMO, UMR 8182, CNRS, Universit ´e
Paris-Saclay, B aˆ t 410, 91405 Orsay, France. E-mail: valerie.alezra@u-psud.fr
†
Electronic supplementary information (ESI) available: Crystallographic data, a
detailed protocol and NRM data of the synthesized compounds are provided.
CCDC 1851456. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c8cc06864j
Scheme 1 Alkylation and aldol reaction by MOC and oxidative coupling
by MOC.
1
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Table 1 Oxidant screening for the enolate coupling between acetophenone
and oxazolidinone 1
Fig. 1 Crystallographic structure of compound 3a.
a
Entry
Oxidant
Solvent
Yield (%)
ee (%)
1
2
3
4
5
6
Cu(2-ethylhexanoate)
2
THF
THF
THF
DMF
DMF
THF
THF
THF
38
18
0
28
0
0
52
7
44
20
—
24
—
—
4
CuCl
Cu(OTf)
Ph IOTf
2
(entries 9 and 10), as well as the replacement of KHMDS by LDA
entries 5 and 6). A decrease of acetophenone improved the
enantiomeric excess without modifying the yield (entries 4 and 5).
On the contrary, a larger quantity of base improved the yield
2
(
2
CAN
AgOTf
b
7
8
Mn(acac)
TiCl
3
(entries 1 and 2, or 5 and 12) although using 6 or 10 equivalents of
4
40
KHMDS gave similar results. Increasing the deprotonation time
a
b
Determined by chiral stationary-phase HPLC. Only 4 equiv. of was beneficial to the yield but induced racemization (entries 5 and
acetophenone were used.
11); in contrast, the oxidation time seemed to have no influence on
the reaction (entries 2 to 4).
observed such as those resulting from autocondensation of
Compound 3a was crystalline (Fig. 1), which allowed con-
acetophenone, or oxidative homocoupling of oxazolidinone 1 firmation of the structure; however the crystal was unfortunately
or of acetophenone. Other oxidants, such as FeCl , FeCp PF , racemic. We thus determined the absolute configuration of
3
2
6
and I , gave either no reaction (FeCl ) or a complex mixture of compound 3a by performing alkylation of compound 1 with
2
3
products. The best results obtained with Cu(2-ethylhexanoate)
are probably partially due to its good solubility in THF at low ESI† for details). The expected compound 3a was obtained
temperature.
in only 10% yield (the electrophile degrades itself rapidly under
We then tried to optimize this reaction and modified the these conditions) and 60% ee. As we previously proved that alky-
2
KHMDS (1.1 equiv.) and bromoacetophenone in THF (see the
39
reaction conditions (Table 2). We studied the influence of the lation reactions occurred with a retention of configuration,
amounts of acetophenone, base, copper and reaction time, as we were able to compare the HPLC chromatograms and thus
well as the use of additives.
confirmed that the major enantiomer issued from enolate oxida-
Although it was previously reported that the aggregation tive coupling has the same configuration as the one obtained via
state is sometimes very important to favor heterocoupling vs. alkylation. Moreover, this experiment showed that in this case,
4
1
homocoupling, the presence of additives that dissociate oxidative coupling is much more efficient than alkylation.
enolate aggregates did not improve the yields or selectivities
This retention of configuration can be explained in the same
way as for alkylation: deprotonation occurs preferentially on
3
9
the major (P,cis) conformer via a dynamic kinetic resolution
(DKR), leading to an enolate with an axial chirality, and then to
Table 2 Optimization of heterocoupling with acetophenone
a radical with the same axial chirality; the other partner attacks
the radical on its less hindered side, opposite to the naphthyl
group leading to global retention of configuration (Scheme 2).
Attempts to react the oxazolidinone radical with acetophone
trimethylsilyl enol ether failed suggesting that an enolate is
a
b
Entry Additive
n
1
n
2
t
1
(min)
n
3
2
t (min) Yield (%) ee (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
—
—
—
—
—
—
—
—
DMPU
TMEDA
—
—
—
5
5
5
5
4
4
4
4
4
4
4
4
3
7
6
6
6
6
6
6
6
6
6
6
3
3
3
3
3
3
3
3
3
3
6
3
3
6
6
6
6
6
6
4
3
3
3
6
6
4
10
10
3
43
38
38
41
45
43
44
32
44
38
63
53
38
46
44
39
40
64
62
65
62
62
62
45
64
60
30
30
30
30
30
30
30
30
30
30
c
0
1
2
3
10
10
a
b
2
.7 equiv. were added with acetophenone. Determined by chiral
c
stationary-phase HPLC. LDA was used instead of KHMDS.
Scheme 2 Explanation of stereoselectivity by MOC.
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mandatory, and that there is probably a copper complexation of Table 4 Scope of heterocoupling with acetyl-heteroaromatics
both intermediates.
We then decided to extend this strategy to substituted
acetophenones to explore the influence of the electron density
of the aromatic group and to enlarge the scope of this reaction.
We also decided to try a protocol with separated deprotonation
(method B) to enable the fine tuning of the deprotonation time
of compounds 2a–e. Temperature and oxidation time were also
modified in order to improve ees and yields. The results are
gathered in Table 3.
a
b
Entry
Method Compound Yield (%) ee (%)
Changing temperature from ꢀ78 1C to ꢀ85 1C has no
influence on the reaction. Modifying the deprotonation method
c
1
B
15
12
60
(replacing method A with method B) increased in most cases
the enantiomeric excess but decreased slightly the yield. On the
contrary, this reaction was found to be strongly dependent on
the electron density of the aromatic ring: although electron-
poor aromatic compounds gave higher yields but lower ees
c
2
A
B
16
0
91
—
c
e
3
16
(
compare entries 2 and 7 or 8), electron-rich aromatic sub-
c
strates gave lower yields but higher ees (compare entries 7 and 10).
The best ees were thus obtained with 4 -methoxy acetophenone or
with 4 -(dimethylamino)acetophenone (71–74%). The yields are
4
A
B
B
46
64
34
87
82
44
0
5
d
6
17
18
0
moderate but in this kind of oxidative heterocoupling, it is often
the case. To explain this link between the yield/enantiomeric
excess and the electron-density, we can propose that deprotonation
occurs faster on an electron-poor compound such as para-nitro
acetophenone, but the enolate is either less reactive towards the
captodative radical generated by oxazolidinone 1 (inducing partial
racemization of the dynamic axial chirality) or less prone to get
oxidized into a radical (both mechanisms can be proposed in our
7
B
43
80
8
9
A
B
24
0
94
—
e
1
2
9
0
1
1
0
1
A
B
57
82
88
81
Table 3 Scope of heterocoupling with substituted acetophenones
1
1
2
3
B
B
21
22
70
21
50
82
a
b
14
15
B
23
75
45
Entry R
Method Temp. (1C) t (min) Compound Yield (%) ee (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
H
H
H
H
NO
NO
NO
Br
OMe
OMe
OMe
NMe
NMe
A
A
A
B
A
B
A
A
A
A
B
A
B
ꢀ78
ꢀ85
ꢀ85
ꢀ78
ꢀ78
ꢀ78
ꢀ85
ꢀ85
ꢀ78
ꢀ85
ꢀ78
ꢀ78
ꢀ78
30
10
30
30
10
10
10
10
10
10
10
30
10
3a
3a
3a
3a
3b
3b
3b
3c
3d
3d
3d
3e
3e
45
44
48
37
73
58
77
60
56
58
38
56
23
64
65
61
64
30
45
32
41
68
60
74
71
44
B
B
24
25
43
58
75
72
16
2
2
2
c
a
Method A: compounds 1 and 4–12 are deprotonated in the same flask,
= 3, n = 10 and n = 4; method B: compounds 1 and 4–12 are
deprotonated in separated flasks, n = 3, n = 7 and n = 4; deprotona-
n
1
2
3
1
2
3
0
1
2
3
tion of 4–12 for 10 min, then deprotonation of 1 for 3 min, and
gathering the two enolates for 3 minutes, then oxidation. Determined
by chiral stationary-phase HPLC. In these cases, n
time was 30 min.
b
c
2
2
= 4 and oxidation
1
d
n
1
= 1.5, n
2
= 5 and n
3
= 3 and oxidation time was
e
a
30 min. No reaction was observed under these conditions.
Method A: n
1
= 4, n
2
= n
3
= 6; compounds 1 and 2 are deprotonated in
= 3, n = 7, n = 4; compounds 1 and 2 are
the same flask; method B: n
1
2
3
deprotonated in separated flasks: deprotonation of 2 for 10 min, then
deprotonation of 1, and gathering the two enolates for 3 min, then
b
c
case as we observed in several experiments either dimers of
compound 1 or dimers of acetophenone as byproducts).
oxidation. Determined by chiral stationary-phase HPLC.
= 8, n = 5.
1
n = 4,
n
2
3
1
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