Highly Enantioselective, Base-Free Synthesis of α-Quaternary Succinimides through Catalytic Asymmetric Allylic Alkylation

Article abstract of DOI:10.1002/chem.201800920

The synthesis of diversely substituted five-membered ring succinimide derivatives is reported featuring a direct, base-free, palladium-catalyzed asymmetric allylic alkylation. The method allows a straightforward access to the desired heterocyclic scaffold bearing an all-carbon α-quaternary stereogenic center in high yields and good to excellent enantioselectivities. To further demonstrate the synthetic utility of the method, the allylated products were further converted to various versatile chiral building blocks, including a chiral pyrrolidine and a spirocyclic derivative, using selective transformations.

Full text of DOI:10.1002/chem.201800920

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Accepted Article
Title: Highly Enantioselective, Base-Free Synthesis of α-Quaternary
Succinimides through Catalytic Asymmetric Allylic Alkylation
Authors: Tao Song, Stellios Arseniyadis, and Janine Cossy
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To be cited as: Chem. Eur. J. 10.1002/chem.201800920
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10.1002/chem.201800920
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Highly Enantioselective, Base-Free Synthesis of -Quaternary
Succinimides through Catalytic Asymmetric Allylic Alkylation
Tao Song,[a] Stellios Arseniyadis*,[a,b] and Janine Cossy*[a]
O
O
O
Abstract: The synthesis of diversely substituted five-membered ring
H
Cl
HN
O
HN
O
succinimide derivatives is reported featuring a direct, base-free,
palladium-catalyzed asymmetric allylic alkylation. The method allows
a straightforward access to the desired heterocyclic scaffold bearing
an all-carbon -quaternary stereogenic center in high yields and
good to excellent enantioselectivities. To further demonstrate the
synthetic utility of the method, the allylated products were further
converted to various versatile chiral building blocks, including a
HN
O
O
Me
O
H
O
H
Me
H
H
Me
Me
H
HO
H
OH
Haterumaimide F
H
H
Me
CO2H
H
Hirsutellone A
Oxaleimide A
Me
O
O
H
O
N
O
N
O
N
Me
HN
Br
chiral pyrrolidine and
transformations.
a spirocyclic derivative, using selective
HN
O
Me
N
MeN
Me
H
H
O
(+)-Ethosuximide
O
Me Me
O
F
Ranirestat
Asperparaline A
Despite the number of methods reported in the literature over
the past decade, the construction of cyclic[1] and acyclic[2]
Figure 1. Typical examples of succinimide-containing natural products and
pharmaceuticals.
frameworks bearing
a quaternary stereogenic center still
remains a particularly challenging task.[3] As a matter of fact,
most of these methods rely on the conjugate addition of a
carbon nucleophile onto a trisubstituted pro-chiral center rather
than on an electrophilic-type functionalization typically
encountered in transition metal-catalyzed asymmetric allylic
alkylation processes.[4]
There are a few enantioselective catalytic methods that allow
a straightforward and highly enantioselective access chiral five
membered ring succinimides bearing a quaternary stereogenic
center at the C3-position; the most common one probably being
the asymmetric Rh-catalyzed 1,4-conjugate addition of
nucleophiles to 3-substituted maleimides (Figure 2, A).[16] This
method has been thoroughly investigated in the last 10 years,
resulting in the development of some particularly effective chiral
catalysts capable of generating the desired 3,3-disubstituted
succinimide derivatives in high enantioselectivities.
For the past several years, we have been focused on
implementing the palladium-catalyzed asymmetric allylic
alkylation (Pd-AAA) to the synthesis of various chiral
heterocycles including chiral isoxazolidin-5-ones,[5] -lactams[5]
butenolides,[6] furanones,[6] butyrolactones,[6,7] 4,5-dihydro
pyrazoles[8] and other diversely substituted 5-, 6-, 7-, 14- and
16-membered ring -phosphono oxaheterocycles[9] all bearing a
quaternary stereogenic center. We logically became interested
in applying this strategy to the synthesis of five membered ring
succinimides. Indeed, this heterocyclic motifs is prevalent in a
number of biologically active natural products such as
hirsutellone A,[10] which was isolated from the insect pathogenic
fungus Hirsutella nivea BCC 2594, the haterumaimides,[11] which
are chlorinated lissoclimide-type diterpenoids isolated from an
Okinawan Lissoclinum sp, asperparaline A,[12] which was
isolated from Aspergillus japonicus JV-23, and oxaleimide A,[13]
isolated from Penicillium oxalicum. This motif is also present in a
number of pharmaceuticals such as the anticonvulsant
ethosuximide[14] and the aldose reductase inhibitor ranirestat.[15]
Another elegant approach leading to chiral 3,3-disubstituted
succinimide building blocks relies on an enantioselective
organocatalytic addition of an -ketoamide onto an
,-unsaturated aldehyde (Figure 2, B).[17] This formal [3+2]
[a]
[b]
Tao Song, Dr. S. Arseniyadis, Prof. Dr. J. Cossy
Laboratoire de Chimie Organique, Institute of Chemistry, Biology
and Innovation (CBI) - ESPCI Paris/CNRS (UMR8231)/PSL*
Research University, 10 rue Vauquelin, 75231 Paris Cedex 05
(France) E-mail: janine.cossy@espci.fr
Dr. S. Arseniyadis
Queen Mary, University of London
School of Biological and Chemical Sciences
Mile End Road, London, E1 4NS (UK)
E-mail: s.arseniyadis@qmul.ac.uk
Supporting information for this article is given via a link at the end of
the document.
Figure 2. Selected strategies for the asymmetric synthesis of chiral
succinimide derivatives.
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Table 1. Systematic study.a
(Figure 2, D). Indeed, if successful, this approach would allow a
straightforward and potentially highly enantioselective access to
enantioenriched succinimides bearing an all carbon
-quaternary stereogenic center.
We initiated our study using the racemic N-benzyl-3-tert-
butylcarboxylate derivative 1a as a model substrate. The latter
was prepared in two steps and 57% overall yield starting from
commercially available succinimide. With compound 1a in hand,
we initiated our study by probing the effect of the experimental
conditions on both the efficiency and the selectivity of the
reaction; these results are depicted in Table 1.
The first parameter to be evaluated was the base. The
reactions were thus run in THF at 0 °C using allyl acetate
(1.0 equiv.), the selected base (2.0 equiv.), Pd2(dba)3 (5.0 mol%)
and Trost’s ligand, (R,R)-L1 (10 mol%), which had previously
given the best selectivities in the Pd-AAA of cyclic dienol
carbonates.[6] As a general trend, all the reactions readily
afforded the corresponding allylated product in moderate to
good enantioselectivities (Table 1, entries 1-9). Interestingly,
both inorganic and organic weak bases led to similar levels of
reactivity and selectivity as exemplified by the ees obtained with
Na2CO3 (77% ee) (Table 1, entry 1), Li2CO3 (76% ee) (Table 1,
entry 2), K2CO3 (78% ee) (Table 1, entry 3) and Et3N (77% ee)
(Table 1, entry 4). In sharp contrast, strong bases such as DBU
(54% ee) (Table 1, entry 5), NaH (20% ee) (Table 1, entry 6),
LDA (20% ee) (Table 1, entry 7) and LiHMDS (33% ee) (Table 1,
entry 8) had a detrimental effect on the enantioselectivity.
Moreover, a reversed selectivity was observed when using LDA
and LiHMDS, which can probably be accounted for by the
structural difference of the corresponding lithium enolates.[20]
Ultimately, the use of 1.0 equiv of Na2CO3 was sufficient to
reach a similar outcome (79% ee) (Table 1, entry 10).
With these results in hand, we next evaluated the influence
of the solvent. Once again, all the reactions afforded the
corresponding allylated product in good yields and moderate to
good enantioselectivities independently of the nature of the
solvent (Table 1, entries 10-17); THF remaining the best among
all the ones that were tested.
Considering the acidity of the -proton and the basicity of the
acetate released during the process, we wondered whether the
reaction could be run in the absence of added base under
otherwise identical conditions. To our delight, we were able to
isolate the corresponding -allylated product in almost
quantitative yield and up to 76% ee (Table 1, entry 18).
Based on this result, we next set out to evaluate the influence of
the chiral ligand. As a general trend, all the reactions proceeded
efficiently, independently of the ligand used. However the chiral
palladium catalysts derived from C2-symmetric bis-phosphines,
such as L1, L2 and L3, displayed higher levels of selectivity
(Table 1, entries 18-20) than the axially dissymmetric C2 chiral
diphosphines, BINAP (L4, 6% ee) (Table 1, entry 21) and
SEGPHOS (L5, 26% ee) (Table 1, entry 22), and the mixed P/N-
type ligands such as the phosphine-oxazoline (PHOX) ligand L6
(21% ee) (Table 1, entry 23). Ultimately, the use of the
(R,R)-DACH-phenyl ligand(L1, 10 mol%) in conjunction with
Pd2(dba)3 (10 mol%) led to the highest level of selectivity,
affording the ,-disubstituted succinimide 3a in 94% yield and
76% ee (Table 1, entry 18). This result could be improved by
cycloaddition relies on the use of chiral NHCs to catalyze the
formation of the corresponding chiral azolium enolate
intermediates and thus promote sufficient facial discrimination to
afford the corresponding chiral succinimide with excellent levels
of enantioselectivity.
Finally, another interesting strategy to prepare these chiral
five-membered ring succinimide derivatives bearing an all-
carbon quaternary center is through
a
copper-catalyzed
-alkylidene
desymmetrization of bis-alkyne-based
a
succinimide precursor (Figure 2, C).[18] A number of effective
chiral ligands[19] were reported to afford the corresponding
-quaternary succinimide derivatives with ees up to 99%,
independently of the aromatic substitution on the alkylidene
moiety.
For our part, we opted for an electrophilic-type
functionalization and envisioned a direct, base-free, Pd-AAA
type reaction applied to 3-substituted succinimide derivatives
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Table 2. Investigation of the reaction scope (Part I).a
Table 3. Investigation of the reaction scope (Part II).a
afforded the corresponding allylated products in roughly the
same selectivity, albeit in slightly lower yields. Unfortunately,
replacing the hydrogen atom by a phenyl (4d, 47% ee) or a
methyl ester (4e, 55% ee) led to much lower enantioselectivities.
Various 3-substituted allyl acetates 2g-v were also evaluated,
notably diversely substituted cinnamyl acetate, which all gave
good to excellent enantioselectivities as exemplified by the ees
obtained for 5a-j ranging from 76% to 96% (Table 4). Hence,
ortho-substituted cinnamyl acetates such as the ones used to
prepare succinimides 5b and 5e gave slightly lower ees than the
ones used to access the meta- (5c and 5f) and para-analogues
(5d and 5g-j) independently of the steric and electronic features
of the substituents. As a general trend, all the para-substituted
cinnamyl acetates, such as the para-methyl (5d, 96% ee), para-
bromo (5g, 89% ee), para-methoxy (5i, 94% ee) and para-
phenyl (5j, 92% ee), afforded the corresponding -allylated
products with higher ees. In addition, cinnamyl acetates bearing
an electron-withdrawing group such as a trifluoromethyl (5h,
77% ee) clearly induced lower enantioselectivities than the ones
featuring an electron-donating substituent such as a methoxy (5i,
94% ee). Most importantly, 3-substituted allyl acetates bearing a
heterocyclic substituent, such as a thiophene (5l, 95% ee) or a
furan (5m, 95% ee), or an aliphatic substituent such as an
n-propyl (5o, 90% ee), all afforded fantastic levels of
enantioselectivity. Interestingly, diallyl acetate only afforded the
mono allylated product 5p in 79% ee albeit in a low 26% yield.
Finally, six-membered ring succinimides could also undergo
allylation under our optimized conditions affording the
corresponding allylated product 5q with up to 73% ee, however
the selectivity dropped as soon as we replaced allyl acetate by
cinnamyl acetate (5r, 44% ee).[21]
performing the reaction at 20 °C without altering the yield
(86% ee) (Table 1, entry 24).
To optimize this Pd-AAA reaction further, we also evaluated
the influence of the allyl donor and found allyl acetate (88% yield,
86% ee) to be superior to allyl benzoate (58% yield, 86% ee)
and allyl methyl carbonate (96% yield, 63% ee), while reducing
the palladium loading from 10 mol% (77% yield, 92% ee) to
2 mol% (41% yield, 93% ee) afforded roughly the same
selectivity but drastically reduced the yield even after
a
prolonged reaction time (up to 65 h) (not shown in the Table;
see Supporting Information for more details).
With an optimal asymmetric reaction protocol in hand
[Pd2(dba)3 (5 mol%), (R,R)-L1 (10 mol%), THF, 20 °C], we next
examined the substrate scope by applying these conditions to
various succinimide derivatives 1a-i. The results are
summarized in Table 2. The first structural element that was
evaluated was the nature of the protecting group on the nitrogen
atom. Preliminary data showed that both electron-rich and
electron-poor benzyl protecting groups led to similar levels of
selectivity (3a-c, ≈ 85% ee). Interestingly, replacing the benzyl
protecting group by a methyl did not alter the selectivity (3d,
87% ee), however we decided to remain with the benzyl
protecting group for the rest of the study. Replacing the tert-butyl
ester at the C3-position by a methyl ester (3e, 19% ee), a phenyl
ester (3f, 44% ee), a benzyl ester (3g, 11% ee) or a para-tolyl
ketone (3h, 48% ee) terribly decreased the selectivity, while the
introduction of the more hindered tert-butyl ketone (3i, 80% ee)
brought the selectivity back to a descent level.
In an effort to broaden the scope of the reaction further, a
variety of 2-substituted allyl acetates 2a-f were engaged in the
allylation process. As the reactions appeared to be more
sluggish, we decided to run them at room temperature instead.
The results are depicted in Table 3. Interestingly, replacing the
hydrogen atom at the C2-position by a methyl (4a, 89% ee), a
trimethylsilyl (4b, 87% ee) or a chlorine atom (4c, 85% ee)
The absolute configuration of the newly formed quaternary
center was later confirmed by single crystal X-Ray analysis of
compound 5g (see structure in Table 4). As a matter of fact, this
stereoselectivity could have also been predicted using the model
proposed by Trost et al.[22] where the enolate approaches
the-allyl palladium-(R,R)-L1 complex by its Re face to avoid
any disfavored steric interaction between the "wall" of the ligand
and the amide moiety of the substrate (Figure 3).
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Table 4. Investigation of the reaction scope (Part III).a
R = Ph
Bn
R = H
O
O
O
O
O
O
H
OH
I2
H
I
I
Bn
Bn
N
N
N
+
CH2Cl2, rt
>99%
Ph
10
O
O
(de = 55%)
(92% ee)
6a
6b
Red-Al
toluene, 0 °C
O
O
O
O
Ot-Bu
O3, CH2Cl2, -78 °C
then PPh3, rt
85%
70%
Ot-Bu
Bn
Bn
N
N
R
O
O
O
O
O
7
3a (R = H, 86% ee)
5a (R = Ph, 92% ee)
Ot-Bu
Bn
(86% ee)
N
O
O
9
O
O
OMe
(86% ee)
Ot-Bu
Bn
H2, Pd/C
EtOAc, rt
98%
N
CO2Me
O
Grubbs II
toluene, rt (55%)
8
(84% ee)
Scheme 1. Derivatization of compounds 3a and 5a.
In summary, we have developed an efficient, base free and
highly enantioselective Pd-AAA process to access chiral
succinimide derivatives bearing an all-carbon -quaternary
stereogenic center. (R,R)-DACH-Phenyl Trost ligand L1 was
found to be the most effective ligand for this reaction, allowing to
generate the desired products in high yields and up to 96% ee.
The absolute configuration of the newly generated stereogenic
center was confirmed by single crystal X-Ray analysis. Most
importantly, the method is highly versatile as it tolerates the use
of a wide variety of substituted allyl acetates. In addition, the
resulting chiral succinimide derivatives can be easily converted
to a number of useful building blocks through simple synthetic
derivatizations.
Experimental Section
General procedure for the Pd-AAA with allyl acetate: To a
solution of Pd2(dba)3 (0.01 mmol, 0.05 equiv) in THF (1 mL) at rt
was added (R,R)-L1 (0.02 mmol, 0.1 equiv) and the mixture was
stirred for 30 min. This solution was then cooled to 0 °C and
transferred via cannula to a flask containing a cooled solution
(0 °C) of 3-substituted succinimide (0.20 mmol, 1.0 equiv) in
THF (1 mL). Once the addition was completed, allyl acetate
(0.20 mmol, 1.0 equiv) was added and the reaction mixture was
stirred at the same temperature until complete consumption of
the starting material (reaction monitored by TLC). The reaction
mixture was eventually filtered through a plug of Celite© and
concentrated under reduced pressure to afford a crude residue,
which was purified by flash column chromatography over silica
gel.
Pd
Pd
1
1
L
L
-
-
)
)
R
R
,
,
R
R
(
(
Re
O
Si
R
R
O
N
O
O
N
Disfavored
P
Favored
P
Figure 3. Proposed stereochemical pathway.
To further demonstrate the synthetic utility of the method, we
converted the allylated products 3a and 5a to various useful
building blocks through simple synthetic procedures (Scheme 1).
Compound 3a was thus subjected to standard iodolactonization
conditions (I2, CH2Cl2, rt). The corresponding spirocyclic
derivatives 6a and 6b where obtained as a mixture of two
diastereoisomers (de = 55%) with no erosion of the
stereochemical integrity of the starting material. The same
compound 3a was also subjected to ozonolysis (O3,
CH2Cl2, 78 °C, then PPh3, rt), hydrogenation (H2, Pd/C, EtOAc,
rt) and cross-metathesis conditions to afford aldehyde 7, the
aliphatic derivative 8 and the disubstituted olefin 9 in 85%, 98%
and 55% yield respectively. Finally, compound 5a was converted
to the corresponding pyrrolidine 10 bearing a quaternary all-
carbon stereogenic center in 70% yield through a Red-Al-
mediated reduction of the two carbonyl moieties.
Acknowledgements
Financial support from the CSC foundation (China Scholarship
Council) is gratefully acknowledged.
Keywords: asymmetric catalysis
•
allylic alkylation
•
succinimides • pyrrolidines • palladium • enantioselectivity
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10.1002/chem.201800920
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Tao Song, Stellios Arseniyadis* and
Janine Cossy*
Page No. – Page No.
Highly Enantioselective, Base-Free,
Synthesis
Succinimides
of
-Quaternary
Catalytic
through
"Who needs a base?" The synthesis of diversely substituted five-membered ring
succinimide derivatives is reported featuring a direct, base free, palladium-
catalyzed asymmetric allylic alkylation. The method allows a straightforward access
to the desired heterocyclic scaffold bearing an all-carbon -quaternary stereogenic
center in high yields and good to excellent enantioselectivities. To further
demonstrate the synthetic utility of the method, the allylated products were further
converted to various versatile chiral building blocks, including a chiral pyrrolidine
and a spirocyclic derivative, using selective transformations.
Asymmetric Allylic Alkylation
This article is protected by copyright. All rights reserved.