Manganese Catalyzed Enantioselective Epoxidation of α,β-Unsaturated Amides with H2O2

Article abstract of DOI:10.1002/adsc.202100198

Herewith, we report the enantioselective epoxidation of electron-deficient cis- and trans-α,β-unsaturated amides with the environmentally benign oxidant H₂O₂. The catalysts - manganese complexes with bis-amino-bis-pyridine and structurally related ligands - exhibit reasonably high efficiency (up to 100 TON) and excellent chemo- and enantioselectivity (up to 100% and 99% ee, respectively). Crucially, the cis-enamides epoxidation enantioselectivity and yield are dramatically enhanced by the presence of NH-moiety, which effect can be explained by the hydrogen bonding interaction between the cis-enamide substrate and the manganese based oxygen transferring species. (Figure presented.).

Full text of DOI:10.1002/adsc.202100198

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DOI: 10.1002/adsc.202100198
Manganese Catalyzed Enantioselective Epoxidation of α,β-
Unsaturated Amides with H O2
2
a,
a
a
Roman V. Ottenbacher, * Vladimir I. Kurganskiy, Evgenii P. Talsi, and
a,
Konstantin P. Bryliakov *
a
Boreskov Institute of Catalysis, Pr. Lavrentieva 5, Novosibirsk 630090, Russian Federation
E-mail: ottenbacher@catalysis.ru; bryliako@catalysis.ru
Manuscript received: February 11, 2021; Revised manuscript received: April 12, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100198
Recently, Huang and co-workers reported manga-
Abstract: Herewith, we report the enantioselective
epoxidation of electron-deficient cis- and trans-α,β-
nese complex bearing chiral N -donor ligand (Figure 1)
4
and its catalytic activity in the enantioselective epox-
unsaturated amides with the environmentally benign
[17]
idation of trans-α,β-unsaturated amides with H O .
2
2
oxidant H O . The catalysts - manganese complexes
2
2
Costas and co-workers contributed a structurally
related manganese catalyst, capable of conducting the
enantioselective epoxidation of β,β-disubstituted enam-
with bis-amino-bis-pyridine and structurally related
ligands - exhibit reasonably high efficiency (up to
1
00 TON) and excellent chemo- and enantioselec-
[18]
ides with H O . Both catalyst systems demonstrated
2
2
tivity (up to 100% and 99% ee, respectively).
Crucially, the cis-enamides epoxidation enantiose-
lectivity and yield are dramatically enhanced by the
presence of NH-moiety, which effect can be
explained by the hydrogen bonding interaction
between the cis-enamide substrate and the manga-
nese based oxygen transferring species.
good to excellent enantioselectivities (up to 99% ee in
a few cases). However, the common drawback of both
systems has been the sophisticated multistep syntheses
of the chiral ligands; furthermore, the applicability of
the above catalysts to the asymmetric epoxidation of
cis-α,β-unsaturated amides has not been examined.
Very recently, Sun and co-workers developed a Mn
catalyst bearing L-proline-derived N -ligand and em-
4
ployed it in the epoxidation of N,N-disubstituted-trans-
Keywords: Enantioselective; Epoxidation; Manga-
nese; Enamide; Hydrogen Peroxide
cinnamamides with THBP as oxidant, affording the
[19]
epoxides in 42–90% yield and 87–99% ee. Herein
we report the catalytic epoxidation procedure relying
on the readily available manganese complexes with
Enantiomerically pure epoxides are ubiquitous inter- bis-amino-bis-pyridine and structurally related ligands
[
20,21]
mediates in organic synthesis, serving as useful 1–4
synthons for accessing functional chiral molecules.
(Figure 1), that exhibit high enantioselectiv-
[1–3]
ities both in cases of trans- and cis-α,β-unsaturated
The epoxides of α,β-unsaturated amides have been amides. The dramatic effect of the N(Alkyl)-H moiety
involved in manufacturing various biologically active on the epoxidation enantioselectivity is discussed in
[4–9]
compounds.
metric epoxidation of α,β-unsaturated amides have so the metal based oxygen transferring species.
far been rather limited. Shibasaki and co-workers First of all, we have identified the optimal epox-
However, effective methods of asym- terms of hydrogen bonding between the substrate and
developed a series of catalyst systems, based on idation conditions, using N,N-dimethylcinnamamide
lanthanide metal complexes, employing TBHP as 5a as substrate, in the presence of catalyst 1 (Table 1).
[10–12]
oxidant
for the asymmetric epoxidation of trans- The reactions were carried out in acetonitrile at
enamides. In recent years, manganese complexes with À 40°C. Using acetic acid as catalytic additive resulted
chiral bis-amino-bis-pyridine and structurally related in the epoxide formation with good asymmetric
ligands have emerged as challenging catalysts for induction (85–86% ee, Table 1, entries 2–4). Catalyst
enantioselective epoxidations of various olefins (un- loading of 1.0 mol% has been found sufficient for
functionalized alkenes, unsaturated ketones and esters) achieving quantitative substrate conversion (Table 1,
with environmentally benign oxidant hydrogen entries 1–4). Replacing acetic acid with the more
[13–16]
peroxide.
sterically demanding additives 2-ethylhexanoic acid
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Figure 1. Mn(II) bis(amino)bis(pyridine) catalysts.
Figure 2. Structures of substrates and additives used in this
study.
[22]
[23]
(EHA)
and 2,2-dimethylbutyric acid (DMBA)
(Figure 2), expectedly, improved the enantioselectivity
up to 98–99% ee (Table 1, entries 5–6). Using 1 mol%
catalyst loading in combination with 8 equiv. of EHA yielded the corresponding epoxides in good yields
vs. substrate) ensured the acceptable yield and (74–97%) and high enantioselectivity (95–98% ee).
enantioselectivity (Table 1, entry 12), so these reaction The presence of bulky alkyl group at the amide moiety
parameters were adopted for subsequent experiments. did not affect the enantioselectivity: substrate 5d
(
Further, the epoxidation of other substrates (Fig- containing NHtBu group showed nearly the same ee as
ure 2) was examined (Table 2). The epoxidation of 5b with the NHMe one (95% vs. 96% ee). The
trans-cinnamic acid amides (Table 2, entries 1–4) epoxidation of cis-enamides in the presence of 1
[a]
Table 1. Optimization of asymmetric epoxidations catalyzed by complex 1.
Entry Catalyst loadings (mol%) Oxidant (equiv. vs. substrate) Additive (equiv. vs. substrate) Conversion [%]/ ee [%]
Yield [%]
(Config.)
1
2
3
4
5
6
7
8
9
1
0.1
0.2
1.0
0.5
0.5
0.5
0.5
0.5
1.0
1.0
1.0
1.0
1.3
1.3
1.3
1.3
1.3
1.3
2.0
3.0
1.3
1.3
1.3
1.3
AcOH (5.0)
AcOH (14.0)
AcOH (5.0)
AcOH (5.0)
EHA (5.0)
DMBA (5.0)
DMBA (5.0)
DMBA (5.0)
DMBA (5.0)
EHA (5.0)
8/8
n.d.
43/38
100/96
65/63
19/18
29/28
15/14
28/27
51/49
63/59
36/34
100/94
85 (2R,3S)
86 (2R,3S)
85 (2R,3S)
99 (2R,3S)
98.5 (2R,3S)
99 (2R,3S)
98 (2R,3S)
98 (2R,3S)
98.5 (2R,3S)
98.5 (2R,3S)
98 (2R,3S)
0
1
1
DMBA (8.0)
EHA (8.0)
1
2
[
a]
Conditions: At À 40°C, [Mn]/[H O ]/[substrate]/[additive]=X μmol:130 μmol:100 μmol:Y μmol in CH CN (0.4 mL), H O
2
2
3
2
2
added by a syringe pump over 30 min. Conversions and yields calculated based on substrate.
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Table 2. Asymmetric epoxidation of enamides with H O
catalyzed by complex 1.
Table 3. Asymmetric epoxidation of enamides with H O
catalyzed by complexes 2, 3 and 4.
2
2
2
2
[a]
[a]
Entry Catalyst Substrate Conversion/Yield (Isolated ee [%]
Entry Substrate Conversion/Yield (Isolated
Yield) [%]
ee [%]
(config.)
Yield) [%]
(config.)
1
2
3
4
5
5a
5b
5c
5e
5f
98/97 (95)
96
1
2
3
5a
5b
5c
100:94 (92)
100:83 (80)
76:74 (68)
98 (2R,3S)
96 (2R,3S)
96.5
(2S,3R)
100/98 (97)
100/100 (96)
70/69 (63)
88/88 (80)
95
(2S,3R)
(2R,3S)
95
[
b]
4
5
6
7
8
9
5d
6a
6b
6c
6d
6e
100:97 (94)
77:70 (58)
100:94 (90)
100:98 (92)
100:100 (95)
100:72 (62)
95 (2R,3S)
(2S,3R)
62
60
86
88
87
2
98.5
(
2S,3R)
99.5
2S,3R)
[b]
(
6
7
8
6d
6e
5a
100/100 (95)
100/75 (61)
100/100 (95)
95
92
97
[a]
Conditions: At À 40°C, [Mn]/[H O ]/[substrate]/[additive]=
2
2
4
μmol:520 μmol:400 μmol:3200 μmol in CH CN (1.6 mL),
3
(2S,3R)
H O added by a syringe pump over 30 min.
2
2
[b]
At À 20°C.
9
1
5b
5c
5f
74/74 (69)
61/61 (55)
100/99 (93)
97.5
(2S,3R)
0
98
(2S,3R)
[b]
proceeded with markedly lower enantioselectivities of 11
2–88% ee (Table 2, entries 5–9). Moreover, in the
99.1
3
(2S,3R)
6
[
c]
1
1
1
1
1
1
1
2
5 g
6a
6b
6c
6d
6e
5a
98/98 (93)
78/73 (62)
86/82 (79)
98/96 (94)
100/94 (91)
100/90 (75)
51/51 (46)
96
88
82
95.5
96
case of cis-enamides, the enantioselectivity showed
strong dependence on the nature of substituents at the
amide functionality. On the one hand, substrates 6c,
3
4
5
6
7
8
6
d and 6e containing NH or different NHAlk groups
2
were epoxidized with virtually the same ee of 86–88%
Table 2, entries 7–9), irrespective of the steric demand
of the alkyl substituent. On the other hand, cis-olefins
a and 6b without NH-fragments afforded epoxides
97
95.5
(
(2R,3S)
6
1
9
5b
5c
92/90 (88)
94.5
(2R,3S)
97
with significantly lower enantioselectivities of 60–62%
ee (Table 2, entries 5 and 6).
20
4
100/99 (95)
Manganese complexes 2, 3 and 4 were also probed
(2R,3S)
76
77
as catalysts in the epoxidation of enamides (Table 3), 21
6b
6c
6d
84/77 (74)
100/76 (70)
100/75 (71)
2
2
2
3
demonstrating good (sometimes quantitative) epoxide
yields. Increasing the steric demand of the catalyst, by
using complex 4, did not lead to enantioselectivity
improvement either in the case of trans- or cis-α,β-
unsaturated amides (entries 18–23 of Table 3). Interest-
ingly, all catalysts, including 1, showed rather similar
enantioselecitvities with trans-enamides (95-99% ee,
cf. entries 1–4 of Table 2 and entries 1–5, 8–11, 18–20
of Table 3), including the enamide analog 5g (4-
quinazolinone derivative, entry 12 of Table 3).
83
[a]
Conditions: At À 40°C, [Mn]/[H O ]/[substrate]/[additive]=
2
2
4
μmol:520 μmol:400 μmol:3200 μmol in CH CN (1.6 mL),
3
H O added by a syringe pump over 30 min.
Additional solvent (CH Cl , 1.6 mL) was added.
Additional solvent (TFE, 4 mL) was added.
2
2
[
b]
c]
2
2
[
epoxidation of cis-enamides (entries 6, 7, 13–17 of
At the same time, catalysts 2 and 3 exhibited Table 3 vs. entries 5–9 of Table 2). Complex 3
improved enantioselectivity (compared with 1) in the displayed the best enantioselectivity in the series (95–
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Scheme 1. Preparative-scale epoxidation of cinnamamide 5c.
9
7% ee) in the oxidation of cis-enamides with NH
groups. This can be ascribed to the effect of strong
electron-donating amino groups at the pyridine moi-
eties of the ligand, which reduces the catalyst electro-
philicity and reactivity, thus resulting in the more
product-like transition state and hence leading to
[20]
enantioselectivity enhancement. Predictably, cis-en-
amides 6a and 6b lacking NÀ H moieties were
epoxidized with lower enantioselection (82-88% ee,
entries 13 and 14 of Table 3), still much higher than in
case of catalyst 1 (60-62% ee, entries 5 and 6 of
Scheme 2. Proposed formation of Mn based oxygen transferring
active species (top), and hydrogen bonding interaction between
[21]
Mn active species and cis-enamide (bottom).
Table 2). The epoxidation of cis-enamides in the efficiently catalyze the enantioselective epoxidations
presence of catalysts 1–4 was found to occur stereo- of trans- and cis-substituted enamides with H O as
2
2
specifically. This is not surprising, given that even the oxidant, using 2-ethylhexanoic acid as additive. The
epoxidation of the very epimerization-prone cis-stil- corresponding epoxides are formed in good yields (up
bene, catalyzed by 1, was highly stereoretentive (cis/ to 100%) and high enantioselectivities (up to 99% ee).
[24]
trans=12).
The scalability of the catalyst system Crucially, in the case of cis-enamide substrates, the
was demonstrated on a preparative-scale epoxidation presence of at least one NÀ H moiety significantly
of cinnamamide 5c (Scheme 1). The corresponding improves the enantioselectivity of epoxidation (from
epoxide was obtained in 95% isolated yield and 95% 60 up to 97% ee). Such effect can be explained in
ee.
terms of hydrogen bonding interaction between the cis-
The observed enantioselectivity pattern in case of enamide substrate and the manganese based oxygen
cis-substrates with NÀ H moieties may indicate the transferring species. Interestingly, such specific inter-
presence of some specific interaction between the cis- action, in the case of cis-enamides with NÀ H moiety,
enamides featuring at least one NÀ H moiety, and the is also crucial for attaining quantitative substrate
V
[16,21,22,25]
putative [(L)(RCOO)Mn =O] active species.
conversion, otherwise unachievable under the condi-
We would expect that such substrate-catalyst interac- tions.
tion could occur via weak hydrogen bonding
(
Scheme 2), which additional stabilization ensures
[
26] Experimental Section
tighter stereocontrol of asymmetric epoxidation.
Such molecular mechanism of stereoselectivity General procedure for the catalytic epoxidation of α,β-
unsaturated amides with H O . In a typical experiment,
substrate (400 μmol) and carboxylic acid (3200 μmol) were
added to the solution of the manganese catalyst (4.0 μmol) in
enhancement well fits within the concept of “biomi-
metic control of chemical selectivity”, archetypical for
biochemical reactions involving enzymes, which bind
and orient the reactant(s).
Overall, bis-amino-bis-pyridine chiral manganese
complexes 1–4 (Figure 1) have been demonstrated to
2
2
[27]
CH CN (1.6 mL), and the mixture was thermostated at the
3
desired temperature. Then, 400 μL of H O solution in CH CN
2
2
3
(
520 μmol of H O ) was injected by a syringe pump over
2 2
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3
0 min upon stirring (300 rpm). The resulting mixture was
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Ohshima, M. Shibasaki, J. Am. Chem. Soc. 2002, 124,
14544–14545.
stirred for 1.5 h at required temperature. The reaction was
quenched with saturated aqueous solution of Na CO and the
2
3
products were extracted with Et O (3×12 mL). The solvent was
evaporated and the residue was analyzed by H NMR
2
[12] S.-Y. Tosaki, R. Tsuji, T. Ohshima, M. Shibasaki, J. Am.
Chem. Soc. 2005, 127, 2147–2155.
1
spectroscopy to determine conversions and yields and by HPLC
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[
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[20b]
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The
absolute configuration was assigned by comparison of HPLC
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[
[
[17]
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The isolated yields were calculated based on
15] R. V. Ottenbacher, Recent Advances in Bioinspired
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[
[
Acknowledgements
2
017, 359, 2535–2541.
This work was supported by the Ministry of Science and Higher
Education of the Russian Federation, project for the Boreskov
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Manganese Catalyzed Enantioselective Epoxidation of α,β-
Unsaturated Amides with H O
2
2
Adv. Synth. Catal. 2021, 363, 1–6
R. V. Ottenbacher*, V. I. Kurganskiy, E. P. Talsi, K. P.
Bryliakov*