Diastereodivergent Asymmetric 1,4-Addition of Oxindoles to Nitroolefins by Using Polyfunctional Nickel-Hydrogen-Bond-Azolium Catalysts

Article abstract of DOI:10.1002/anie.201502930

Diastereodivergency is a challenge for catalytic asymmetric synthesis. For many reaction types, the generation of one diastereomer is inherently preferred, while the other diastereomers are not directly accessible with high efficiency and require circuitous synthetic approaches. Overwriting the inherent preference by means of a catalyst requires control over the spatial positions of both reaction partners. We report a novel polyfunctional catalyst type in which a Ni^II-bis(phenoxyimine) unit, free hydroxy groups, and an axially chiral bisimidazolium entity participate in the stereocontrol of the direct 1,4-addition of oxindoles to nitroolefins. Both epimers of the 1,4-adduct are accessible in excess on demand by changes to the ligand constitution and configuration. As the products have been reported to be valuable precursors to indole alkaloids, this method should allow access to their epimeric derivatives.

Full text of DOI:10.1002/anie.201502930

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201502930
German Edition: DOI: 10.1002/ange.201502930
Cooperative Catalysis
Diastereodivergent Asymmetric 1,4-Addition of Oxindoles to
Nitroolefins by Using Polyfunctional Nickel-Hydrogen-Bond-Azolium
Catalysts**
Melanie Mechler and RenØ Peters*
Abstract: Diastereodivergency is a challenge for catalytic
asymmetric synthesis. For many reaction types, the generation
of one diastereomer is inherently preferred, while the other
diastereomers are not directly accessible with high efficiency
and require circuitous synthetic approaches. Overwriting the
inherent preference by means of a catalyst requires control over
the spatial positions of both reaction partners. We report
a novel polyfunctional catalyst type in which a NiII-bis(phen-
oxyimine) unit, free hydroxy groups, and an axially chiral
bisimidazolium entity participate in the stereocontrol of the
direct 1,4-addition of oxindoles to nitroolefins. Both epimers of
the 1,4-adduct are accessible in excess on demand by changes
to the ligand constitution and configuration. As the products
have been reported to be valuable precursors to indole
alkaloids, this method should allow access to their epimeric
derivatives.
nitroolefins. This reaction type has been intensively studied in
the last few years[5] because chiral oxindoles are both
ubiquitous in nature and the products represent valuable
building blocks for alkaloid syntheses.[6] Despite the growing
number of reported methods for the direct 1,4-addition of 3-
alkyl oxindoles to nitroolefins, all of them have in common
that product diastereomers with identical relative configura-
tion are formed in excess,[5] while no efficient route is
currently known for the epimeric product series.
We created a polyfunctional catalyst design featuring
a NiII-bis(phenoxyimine) unit equipped with free OH groups
and an axially chiral bisimidazolium moiety as a chiral linker
(Figure 1). We anticipated that cooperative catalysis might
C
hiral compounds with a nonsymmetric constitution featur-
ing n stereocenters can, in principal, exist as 2n different
stereoisomers, that is, 2nÀ1 enantiomeric pairs of diastereo-
mers.[1] For many reaction types, the formation of one of these
diastereomers is inherently preferred,[2] while efficient direct
access to the other diastereomers (here called “unnatural”
diastereomers) very often represents an unsolved problem.
The number of catalytic asymmetric methods for diastereo-
divergent access to all possible diastereomers is, in general,
still quite small.[3] Catalytic systems capable of switching the
diastereoselectivity outcome on demand require special
strategies, which are different from more traditional catalyst
designs to overcome the inherent stereochemical preferences.
The development of such catalysts is an important task,
because both the absolute and relative configurations have an
impact on the properties of a compound, for example, in
terms of its physiological activity.[4]
Figure 1. General design of the polyfunctional catalysts 1-X.
create new opportunities for a diastereodivergent bond-
forming process,[7] because the simultaneous interaction of
both substrates with the different activating groups of
a polyfunctional catalyst should allow both reactants to be
preorganized in a defined manner in space during the
stereoselectivity-determining step. While the NiII-bis(phen-
oxyimine) entity in 1-X (XÀ indicates the counterion) might
serve as a Lewis acid/Brønsted base to trigger the oxindole
enolization, the nitroolefin might be activated simultaneously
by hydrogen bonds.[8] The bisimidazolium linker might also
allow for electrostatic and/or p interactions.[9] The interplay of
different chirality elements within the catalyst should provide
additional handles for control of the relative spatial positions
of both substrates in the reactive catalyst species.
The synthesis of 1-Cl is readily accomplished in three steps
(Scheme 1) starting from the axially chiral bisimidazole 2[10]
and benzyl chloride 3,[11] which were applied to a double SN2-
alkylation to provide 4.[10,12] A subsequent diimine generation
using enantiopure b-aminoalcohols followed by coordination
to NiII provided the complexes 1-Cl in very high overall
yields.[13]
Here we describe a modular polyfunctional catalyst
concept which allows enantioselective access to both possible
sets of diastereomers in the direct 1,4-addition of oxindoles to
[*] Dipl.-Chem. M. Mechler, Prof. Dr. R. Peters
Universität Stuttgart, Institut für Organische Chemie
Pfaffenwaldring 55, 70569 Stuttgart (Germany)
E-mail: rene.peters@oc.uni-stuttgart.de
[**] This work was financially supported by the Deutsche Forschungs-
gemeinschaft (DFG, PE 818/3-1). We thank Dr. Mark Ringenberg
and Dr. Martina Bubrin (Kaim group, Institut für Anorganische
Chemie, Universität Stuttgart) for recording the UV/Vis spectra and
Dr. Wolfgang Frey (Institut für Organische Chemie, Universität
Stuttgart) for the X-ray crystal structure analysis of 7a-D1.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201502930.
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Table 1: Catalyst screening.
Yield
D1/
ee D1 ee D2
Entry
1-X
7a [%][a] D2[b]
[%][c]
[%][c]
Scheme 1. Synthesis of the catalysts 1-Cl.
1
2
3
4
1a-Cl[d]
1a-BF4
1a-O2CC3F7 63
>99
>99
73:27 86
79:21 97
63:37 67
46:54 38
31
62
30
14
The complexes 1-Cl were then investigated in the direct
1,4-addition of oxindole 6a to 2-nitrostyrene (5a) in CH2Cl2
at room temperature in the presence of 5 mol% 1-Cl
(Table 1). Various iminoalcohol motifs were surveyed, which
differed in their configurations and residues R1–R3.
1a-OAc
>99
5
6
7
8
1b-Cl[d]
1b-BF4
1b-O2CC3F7 68
>99
>99
20:80 64
17:83 69
15:85 11
30:70 14
87
91
61
47
Proof of principle was established with the (1R,2S)- and
the (1S,2R)-norephedrine-derived complexes 1b-Cl and 1c-
Cl, respectively. Whereas 1b-Cl primarily produced the
natural diastereomer D2 of 7a (Table 1, entry 5), the unnatu-
ral epimer D1 was generated in excess with 1c-Cl (Table 1,
entry 9).[14] Improved diastereoselectivity favoring D1 was
noted with 1a-Cl derived from (1S,2R)-1,2-diphenyl-2-amino-
ethanol (Table 1, entry 1). Different silver salts were surveyed
for a chloride exchange with 1a-Cl and 1b-Cl. Anions with
1b-OAc
>99
9
1c-Cl[d]
1d-Cl[d]
1e-Cl[d]
1 f-Cl[d]
1g-Cl[d]
1h-Cl[d]
>99
>99
>99
>99
>99
>99
65:35 86
16:84 40
43:57 51
24:76 61
34:66 21
40:60 25
32
86
39
72
11
13
10
11
12
13
14
À
low Lewis/Brønsted basicity such as BF4 further improved
the stereoselectivities of both catalysts (Table 1, entries 2 and
À
6). Very similar data were obtained for XÀ = triflate and PF6
(not shown). In contrast, carboxylate counterions led to
decreased stereoselectivities (Table 1, entries 3, 4, 7, and 8).
Catalysts with different iminoalcohol motifs were exam-
ined to understand the influence of the individual chirality
elements. The catalysts 1d-Cl and 1e-Cl derived from (R)-
and (S)-1-phenyl-2-aminoethanol, respectively, containing
one stereocenter at the 1-position of the iminoalcohol side
chains both favored D2 (Table 1, entries 10 and 11) and only
1d-Cl formed D2 with good diastereo- and enantioselectivity.
Catalysts 1 f-Cl and 1g-Cl derived from (R)- and (S)-phenyl-
glycinol, respectively, also both favored D2 (Table 1,
entries 12 and 13). Enantioselectivity was poor with 1g-Cl.
Similar data were obtained with 1h-Cl derived from 1S,2S-
configured 1,2-diphenyl-2-aminoethanol (Table 1, entry 14).
These results show that both stereocenters in the 1S,2R-
configured iminoalcohol motifs in 1a-Cl and 1c-Cl are
necessary for a switch to the unnatural diastereomer. It is
also noteworthy that all the catalysts reported in Table 1
generated the same major enantiomers for D1 and D2. This
indicates that the axially chiral bisimidazolium backbone
plays the dominant role with regard to the enantiocontrol in
a matched/mismatched system.
[a] Yield of 7a determined by 1H NMR spectroscopy using an internal
standard. [b] Diastereomeric ratio of 7a determined by 1H NMR
spectroscopic analysis of the crude product. [c] Enantiomeric excess of
7a determined by HPLC. [d] No Ag salt was used.
diastereomers were produced with poor to low enantioselec-
tivity (Table 2, entries 1, 2, and 8). Similar results were
obtained for catalysts 9 and 9ꢀ with axially chiral, yet neutral
(R)- and (S)-1,1ꢀ-bi-2-naphthol (BINOL) based linkers
(Table 2, entries 3, 4, and 9). These results suggest that the
bisimidazolium actively participates in the stereocontrol.
Moreover, the control experiments with catalysts 10 (Mes =
mesityl) featuring two independent imidazolium-containing
phenoxyimine moieties (Table 2, entries 5 and 10) confirm
that the axially chiral linker is an important factor for the
observed switch in diastereoselectivity for catalysts 1a and 1c,
as catalysts 10 both generate the natural diastereomer D2. It
is also remarkable that catalysts 1a and 10a display enantio-
divergency and generate D2 with the opposite absolute
configuration. Similar phenomena were observed with the use
of catalysts 11a and 11b (Table 2, entries 6 and 11), which
have been prepared from an optically inactive biphenylbis-
imidazole. The natural diastereomer D2 was also formed in
Various control systems were studied to learn more about
the impact of the imidazolium linker (Table 2). The flexibility
of the axially chiral bisimidazolium appears to be important
for the observed diastereodivergency, because control experi-
ments using bisimidazolium catalysts 8 and 8’ that feature
a more rigid cyclohexane-1,2-diyl backbone always provided
D2 in excess, irrespective of the iminoalcohol residues. Both
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Table 2: Study of different control systems.
Table 3: Diastereodivergency for different substrates.
Entry 1-BF4
7
R1
R2 Yield [%][b] D1/D2[c] ee [%][d]
1
2
1a-BF4
1b-BF4
96 (>99)
>99 (>99) 10:90
79:21
97
94
7a Ph
Me
Me
3
4
1a-BF4
1b-BF4
>99 (>99) 77:23
89 (91)
92
91
7b 4-Me-C6H4
13:87
5
6
1a-BF4
1b-BF4
97 (>99)
95 (98)
78:22
27:73
88
89
Entry Catalyst
R
Yield
[%][a]
D1/
ee D1
ee D2
7c 4-MeO-C6H4 Me
D2[b]
[%][c]
[%][c]
1
2
3
4
5
6
7
8a
8’a
9a
9’a
10a
11a
12a
>99
60
36:64
26:74
15:85
18:82
14:86
28:72
69:31
À9
7
21
0
16
27
86
3
7
8
1a-BF4
1b-BF4
82 (97)
66 (90)
72:28
11:89
93
88
7d 4-Br-C6H4
7e 2-Cl-C6H4
Me
Me
À18
À30
À25
À79
À70
45
>99
>99
>99
>99
>99
9
10
1a-BF4
1b-BF4
72 (93)
60 (81)
94:6
34:66
95
94
11
12
1a-BF4
1b-BF4
93 (93)
83 (83)
76:24
12:88
95
85
7 f 4-O2N-C6H4 Me
7g 3-O2N-C6H4 Me
8
9
10
11
12
8b
9b
10b
11b
12b
>99
>99
>99
>99
>99
32:68
15:85
15:85
24:76
14:86
À41
16
À15
À27
71
40
54
69
79
89
13
14
1a-BF4
1b-BF4
90 (93)
66 (75)
80:20
15:85
97
90
15
16
1a-BF4
1b-BF4
96 (>99)
91 (93)
80:20
12:88
96
89
7h 2-furyl
7i iPr
Me
Me
Et
17[e] 1a-BF4
18[e] 1b-BF4
42 (42)
77 (77)
70:30
17:83
74
90
13
13
68
36:64
À20
2
[a–c] See Table 1. A minus sign for ee values indicates that the antipode
to the depicted enantiomer was formed in excess.
19
20
1a-BF4
1b-BF4
80 (80)
95 (96)
60:40
13:87
95
57
7j Ph
[a] All reactions with 1b-BF4 were carried out in the presence of 10 mol%
HOAc. [b] Yield of isolated product 7 (in brackets, yield determined by
1H NMR spectroscopy using an internal standard). [c] Diastereomeric
ratio determined by 1H NMR spectroscopic analysis of the crude
product. [d] Enantiomeric excess of the major diastereomer determined
by HPLC. [e] Reaction in 1,2-dichloroethane at 808C.
excess with these two catalysts. The importance of an axially
chiral bisimidazolium linker is further supported by the
results obtained with catalysts 12a and 12b, which feature an
R-configured [1,1’-binaphthalene]-2,2’-diamine (BINAM)
based backbone. Catalysts 12a and 12b show similar stereo-
selectivity trends as their counterparts 1a and 1b. Complex
12a thus also allows for the preferred formation of the
unnatural diastereomer D1 with good enantioselectivity,
whereas 12b forms mainly D2 with good enantioselectivity
(Table 2, entries 7 and 12).
Control experiments with catalyst 13, in which the OH
groups of 1a-Cl are protected as methyl ethers (Table 2,
entry 13), revealed that, in contrast to the use of 1a-Cl,
product 7a-D2 is formed in excess. The reactivity is also much
lower in this case, thus indicating that activation by hydrogen
bonding through the OH groups is an important factor.
To probe the generality of the diastereodivergency 1a-BF4
and 1b-BF4 were applied to various substrate combinations
(Table 3). Since we found that the reactions catalyzed by 1b-
BF4 showed a somewhat higher stereoselectivity in the
presence of catalytic amounts of HOAc (not shown above),
all entries in Table 3 with this catalyst were carried out with
HOAc, while 1a-BF4 performed better in the absence of
HOAc. A switch of the dominant diastereomer was observed
in all investigated examples.
Similar reactivity as well as diastereo- and enantioselec-
tivity to those with model substrate 5a were observed for
nitroolefins 5 equipped with s and p donors (Table 3,
entries 3 and 4 and 5 and 6, respectively) on aromatic residues
R1. Nitroolefins with s and p acceptors on R1 were also well
tolerated and provided high enantioselectivities (Table 3,
entries 7–14). The highest preference for the unnatural
diastereomer D1 was found for an ortho-substituted Michael
acceptor (Table 3, entry 9).
The catalyst systems can also be applied to nitroolefins
carrying heterocycles, such as furyl, and alkyl chains, such as
iPr (Table 1, entries 15–18). Although the results for the latter
substrates using 1a-BF4 were inferior in terms of reactivity
and stereoselectivity to those obtained with 1b-BF4, the
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number of examples for alkyl-substituted nitroalkenes is, in
general, small and a-branched alkyl residues have, to our
knowledge, not yet been described.[5c,e] In addition, R2 = Et
was also tolerated (Table 3, entries 19 and 20). Although D2
was formed with only a moderate ee value in that case
(Table 3, entry 20), D1 was still formed with high enantiose-
lectivity (Table 3, entry 19).
of the different chirality elements. The axially chiral bisimid-
azolium determines the configuration of the stereocenter
generated at the nitroolefin, while the constitution as well as
the relative and absolute configuration of the iminoalcohol
side arms mainly control the stereocenter generated at the
oxindole. The application of related polyfunctional catalysts
to other reaction types is currently in progress.
The observed diastereodivergency might be explained by
a mechanism in which the Ni centers, OH groups, and the
bisimidazolium moieties cooperate (Figure 2). A control
Keywords: axial chirality · cooperative catalysis ·
hydrogen bonds · imidazolium · oxindoles
How to cite: Angew. Chem. Int. Ed. 2015, 54, 10303–10307
Angew. Chem. 2015, 127, 10442–10446
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Figure 2. Simplified working model: whereas the preferred spatial
orientation of the nitroolefin is mainly determined by the axially chiral
bisimidazolium linker and thus similar for catalysts 1a (left) and 1b
(right), the reactive orientation of the nucleophile depends on the
iminoalcohol side chain (only the iminoalcohol moiety involved in
a hydrogen bond with the substrate is shown for simplicity).
experiment with an N-methyloxindole resulted in no 1,4-
adduct. We thus suggest a scenario in which oxindole
enolization is triggered by bidentate coordination of the
carbonyl group to NiII. As shown above, changes within the
iminoalcohol side arms have an influence on the preferred
configuration of the stereocenter at the oxindole. The
À
orientation of the oxindole in the C C bond-forming
transition state might thus be dictated by the iminoalcohol
moieties, whereas the preferred configuration of the gener-
ated stereocenter in the nitroalkane chain is always identical
when using the Ra-configured bisimidazolium linker. For that
reason, we suggest that the nitroolefin is activated by
hydrogen bonds/electrostatic interactions with the bisimida-
zolium groups,[15] whereas the free hydroxy groups might be
important to control the reactive conformation of the
oxindole-NiII adduct (Figure 2). It should be noted that the
iminoalcohol side chains can be symmetrically inequivalent
after substrate coordination. The flexibility of an axially chiral
bisimidazolium linker might be beneficial to readily adopt the
optimal positions of both reacting centers.
[7] Cooperative Catalysis (Ed.: R. Peters), Wiley-VCH, Weinheim,
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[8] Overview of hydrogen bonds in cooperative catalysis: X. Lu, L.
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[9] Onium salts in cooperative catalysis: M. Waser, J. Novacek, K.
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[10] M. Mechler, W. Frey, R. Peters, Organometallics 2014, 33, 5492.
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In conclusion, we have developed a polyfunctional, read-
ily available novel catalyst type which is capable of over-
writing the inherent diastereoselectivity in direct 1,4-addi-
tions of oxindoles to nitroolefins to give rise to the epimeric
product series, which was previously not accessible. Crucial
for the switch in diastereoselectivity is the interplay of a Lewis
acid, free hydroxy groups, and an axially chiral bisimidazo-
lium linker in combination with the appropriate arrangement
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absolute configuration of 7a-D2 was assigned by comparison to
the literature data (see Ref. [5]).
[15] Recent reviews describing CH···X hydrogen bonds using azo-
lium salts as hydrogen-bond donors: a) J. Cai, J. L. Sessler,
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[13] The structure of paramagnetic 1-Cl is supported by ESI-MS, IR
and UV/Vis spectroscopy as well as microanalyses. Moreover,
deuteration experiments confirm that Ni-NHC (NHC = N-
heterocyclic carbine) complexes have not been generated,
because treatment of 1-Cl with PPh3 in the presence of 2 equiv
of 2H-OAc in CH2Cl2 regenerated the ligand with no deuterium
incorporation in the bisimidazolium part, as determined by
1H NMR spectroscopy.
[14] The absolute configuration of 7a-D1 was determined by X-ray
crystal-structure analysis. CCDC 1054807 contains the supple-
mentary crystallographic data. These data are provided free of
charge by The Cambridge Crystallographic Data Centre. The
Received: March 30, 2015
Published online: June 26, 2015
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