An asymmetric aerobic aza-Wacker-type cyclization: Synthesis of isoindolinones bearing tetrasubstituted carbon stereocenters

Article abstract of DOI:10.1002/anie.201203693

It's all in the solvent: An enantioselective variant of an aza-Wacker-type cyclization that gives isoindolinones containing tetrasubstituted carbon centers α to the nitrogen atom has been developed (see scheme; tfa=trifluoroacetate). The use of a highly coordinating solvent is crucial for the activity of the catalyst and the stereoselectivity the reaction (up to 99 % ee). Copyright

Full text of DOI:10.1002/anie.201203693

Angewandte
Chemie
DOI: 10.1002/anie.201203693
Asymmetric Catalysis
An Asymmetric Aerobic Aza-Wacker-Type Cyclization: Synthesis of
Isoindolinones Bearing Tetrasubstituted Carbon Stereocenters**
Guoqiang Yang, Chaoren Shen, and Wanbin Zhang*
Chiral amines bearing an a-tetrasubstituted carbon stereo-
center are important structural motifs of potent drugs and
bioactive natural products, and therefore, considerable effort
enantioselective aza-Wacker-type reactions that give chiral
amines bearing an a-tetrasubstituted carbon stereocenter
have not yet been established, despite some success in
preparing such compounds in other metal-catalyzed intra-
molecular oxidative-amination reactions.[8–10] Herein, we
describe an asymmetric palladium-catalyzed aza-Wacker-
type cyclization that gives isoindolinones that contain a tetra-
substituted carbon stereocenter a to the nitrogen atom.
Recently, we developed a regioselective intramolecular
aerobic aza-Wacker-type cyclization for the preparation of
isoindolinones and isoquinolin-1(2H)-ones; trisubstituted
olefin substrates were highly reactive under the reaction
conditions (Pd(OAc)2/1,10-phenanthroline/MeOH/O2/608C)
and gave isoindolinone products bearing tetrasubstituted
carbon atoms a to the nitrogen atom.[15] We believed that an
enantioselective variant of this reaction could be developed.
These chiral isoindolinones can be found as structural motifs
in biologically active natural products and drug candidates
such as 1,[16a] which is a renin inhibitor, 2,[16b] which is a drug
for the treatment of cardiac arrhythmias, and 3, which is
a modulator of serotonin receptors (Figure 1).[16c]
has been directed toward their asymmetric synthesis.[1]
A
variety of useful asymmetric catalytic reactions involving the
addition of nucleophiles to ketimines has been reported.[1,2]
However, the transition-metal-catalyzed amination of
alkenes to give chiral amines bearing an a-tetrasubstituted
carbon stereocenter, remains unexploited and challenging.[3]
Intramolecular amination of alkenes has attracted much
attention because of the importance of nitrogen-containing
heterocycles.[4–12] Oxidative aza cyclizations and their enan-
tioselective variants are some of the most efficient intra-
molecular amination reactions.[6,7] The research group of
Chemler has developed a family of elegant copper-catalyzed
asymmetric intramolecular oxidative-amination reactions of
alkenes, reactions that include haloamination,[8a] carboami-
nation,[8b,c] aminooxygenation,[8d,e] and diamination.[8f] In
addition, the research group of Yang has shown that it is
possible to form two stereocenters in a highly enantioselective
palladium-catalyzed aerobic tandem aza cyclization/Heck-
type reaction.[9] Enantioselective palladium-catalyzed oxida-
tive-aminocarbonylation reactions have
also
been
reported.[10] However, the use of these catalytic asymmetric
reactions is limited to the preparation of chiral cyclic amines
bearing an a-trisubstituted carbon stereocenter.
Palladium-catalyzed aza-Wacker-type cyclizations are of
longstanding interest.[11,12] Despite recent advances in this
area,[12] efforts toward the development of enantioselective
variants have had limited success, and highly enantioselective
aza-Wacker-type cyclizations have only recently become
feasible.[13] In contrast, asymmetric Wacker-type cyclizations
have been relatively well-studied.[14] Whereas previously
developed enantioselective aza-Wacker-type cyclizations
gave amines bearing an a-trisubstitued carbon stereocenter,
Figure 1. Representative examples of isoindolinones bearing tetrasub-
stituted carbon stereocenters a to the nitrogen atom.
In initial attempts to effect the transformation, we tested
reaction conditions used previously by both our research
group (MeOH/O2)[15] and the research groups of others
(toluene/O2; Scheme 1).[9,13] When using the chiral pyridine–
oxazoline ligand, iPr-Pyrox, together with Pd(OAc)2 as the
metal source, the transformation of substrate 4 was much
more efficient in MeOH than it was in toluene and the
product was isolated with a moderate ee value. We decided to
use a more reactive substrate, and chose compound 6, which is
[*] G. Yang, C. Shen, Prof. W. Zhang
School of Chemistry and Chemical Engineering
Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai 200240 (China)
E-mail: wanbin@sjtu.edu.cn
Homepage: http://wanbin.sjtu.edu.cn
[**] We thank Prof. Tsuneo Imamoto and Dr. Masashi Sugiya for helpful
discussions. This work was partially supported by the National
Natural Science Foundation of China (No. 20972095 and
21172143), the Science and Technology Commission of Shanghai
Municipality (No. 10dz1910105), and Nippon Chemical Industrial
Co. Ltd. We would also like to thank members of the Instrumental
Analysis Center of Shanghai Jiao Tong University.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203693.
Scheme 1. Initial experiments to explore the catalytic reaction.
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Table 1: A solvent screen.[a]
Table 2: Further optimization of reaction conditions.[a]
Entry
Solvent
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
toluene
DCE
1,4-dioxane
MeOH
EtOH
24
24
24
12
12
24
24
24
12
24
24
24
12
12
71
68
65
99
98
73
46
81
95
78
75
94
90
99
21
54
24
66
52
47
35
29
70
67
66
57
68
79
Entry
Substrate
PdII
L*
t [h]
ee [%][b]
1
6
6
6
6
6
6
6
6
8a
8a
8a
8a
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(tfa)2
Pd(tfa)2
Pd(tfa)2
Pd(tfa)2
Pd(tfa)2
Pd(tfa)2
Pd(tfa)2
iPr-pyrox
iPr-quinox
Ph-pyrox
Bn-pyrox
tBu-pyrox
tBu-pyrox
tBu-pyrox
tBu-pyrox
tBu-pyrox
Bn-pyrox
tBu-pyrox
tBu-pyrox
12
24
12
12
12
10
4
48
3
3
79
9
2[c]
3
59
81
81
89
94
95
97
85
96
86
iPrOH
4
5
6
tAmylOH
CF3CH2OH
DMF
DMA
NMP
acetone
DMSO
MeCN
7[d]
8[d,e]
9[d]
10[d]
11[d,f]
12[d,g]
9
10
11
12
13
14
9
96
[a] Reactions were carried out on a 0.20 mmol scale using Pd(OAc)2
(10 mol%) and ligand (20 mol%) in solvent (2.0 mL) under O2 (1 atm)
at 608C. [b] Yield of isolated product. [c] Determined by HPLC using
a chiral stationary phase. Bn=benzyl, DCE=dichloroethane,
DMA=N,N-dimethylacetamide, DMF=N,N-dimethylformamide,
DMSO=dimethylsulfoxide, NMP=N-methylpyrrolidinone.
[a] Unless otherwise stated, reactions were carried out on a 0.20 mmol
scale using 10 mol% PdII and 20 mol% ligand in MeCN (2.0 mL) under
1 atm dioxygen at 608C. Yields of isolated product were 99%.
[b] Determined by HPLC using a chiral stationary phase. [c] Yield was
61%. [d] 4 ꢀ molecular sieves (80 mg) was added. [e] Reaction temper-
ature was 308C and the yield was 81%. [f] PdII (5.0 mol%) and ligand
(7.5 mol%) were used. [g] PdII (1.0 mol%) and ligand (1.2 mol%) were
used and the yield was 76%. tfa=trifluoroacetate.
different from compound 4 in that it contains the more
electron-withdrawing and easily removable N-OBn group
(Table 1).[14e,g] Again, the reaction was more efficient in
MeOH than it was in toluene (Table 1, entries 1 and 4).[17] We
then screened different solvents to improve the enantiose-
lectivity (Table 1). The use of strongly coordinating solvents
gave the best yields and the highest levels of enantioselectiv-
ity; for example, when the reaction was performed in solvents
such as MeOH, DMF, and DMSO, the results were better
than when it was performed in toluene, DCE, and 1,4-dioxane
(Table 1, compare entries 4, 9, and 13 with entries 1–3). The
use of alcohol solvents with smaller alkyl group gave products
with higher ee values (Table 1, entries 4–7). The enantiose-
lectivity of the reaction appears to be adversely affected by
solvents of relatively high acidity: when the solvent is changed
from ethanol to the isosteric yet more acidic solvent,
CF3CH2OH, the ee value of the product drops from 52 to
29% (Table 1, entries 5 and 8). Among the acyl-containing
solvents, the use of DMF provided the best result (Table 1,
entries 9–12). The highest level of enantioselectivity was
achieved when using MeCN as the solvent, a result that may
due to its small size and its ability to coordinate strongly
through its nitrogen atom (Table 1, entry 14).
enantioselectivity of the reaction could be further enhanced
by changing the metal source from Pd(OAc)2 to Pd(tfa)2 and
by adding molecular sieves (Table 2, entries 6 and 7). Unlike
the previously reported asymmetric aza-Wacker-type cycliza-
tion,[13] reducing the reaction temperature did not lead to
a significant increase in the ee value (Table 2, entry 8). This
result may be due to the difficulty of MeCN in dissociating
from the metal center of the catalyst or a catalytic inter-
mediate at low temperature.[18] The use of substrate 8a, which
has a relatively small N protecting group (N-OMe), gave
a higher ee value (Table 2, entry 9). The use of the ligand, Bn-
Pyrox, gave a lower level of enantioselectivity than that of
tBu-Pyrox under the same reaction conditions (Table 2,
entry 10). Decreasing the catalyst loading from 10 to
5 mol% did not obviously affect the results (Table 2,
entry 11). The catalyst amount could be further decreased
to 1 mol% without a significant decrease in enantioselectivity
if the reaction time was increased (Table 2, entry 12). Based
on the above results, the optimized reaction conditions are as
follows: tBu-Pyrox (7.5 mol%) as the chiral ligand, Pd(tfa)2
(5.0 mol%) as the palladium source, MeCN as the solvent,
4 ꢀ molecular sieves as an additive, and 608C as the reaction
temperature.
With the optimum solvent established, we then screened
other variables such as metal source, ligand, and time of
reaction (Table 2). When using Pd(OAc)2 as the palladium
source, without an additive, the use of tBu-Pyrox and Bn-
Pyrox as ligands provided the highest ee values (Table 2,
entries 1–5). The use of the sterically hindered quinolone–
oxazoline ligand, iPr-Quinox, gave a low yield and a low level
of enantioselectivity (Table 2, entry 2).[13] The efficiency and
Having optimized reaction conditions established, a vari-
ety of substrates were examined (Table 3). The use of
substrates containing different terminal substituents on the
olefin moiety gave quantitative yields and good levels of
enantioselectivity (Table 3, entries 1–4). When the terminal
substituent of the olefin moiety in the substrate was an ethyl
or a 2-phenylethyl group, a mixture of olefin isomers were
2
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Table 3: Substrate scope.[a,b,c]
presence of an electron-donating group on the benzene ring
led to a decrease in both the yield and the enantioselectivity
(Table 3, entries 9, 12, and 13); on the other hand, the
presence of an electron-withdrawing group showed no effect
on the results (Table 3, entries 10 and 11). Substitution at the
position ortho to the acyl group is also tolerated, but the
reactivity of the corresponding substrate 8m is relatively low
(36 h, 71% yield; Table 3, entry 13). Although the reaction of
substrate 8n, which contains a substituent at the position
ortho to the olefin group, was efficient, the ee value of the
product was relatively low (57%) owing to the E geometry of
the olefin moiety (Table 3, entry 14).[17,19]
Entry
8
t [h]
9 ee [%] (Yield [%])
9
1
8a
8b
9a: 96 (99)
2
3
9
9
9
9b: 96 (33)
9c: 96 (74)
9b’: 99 (66)
9c’: 98 (25)
The absolute configuration of the product 9j was deter-
mined to be S by X-ray crystallographic analysis (Figure 2).[20]
This stereochemical outcome can be explained using the
model of Stahl and co-workers (Scheme 2).[13c] The nitrogen
8c
8d
4
9d: 94 (95)
5
6
7
8
8e: R=Et
8 f: R=nPr
8g: R=CH2CH2Ph
8h: R=cyclopentyl
9
9
9
9
9e: 94 (99)
9 f: 94 (99)
9g: 92 (99)
9h: 91 (99)
Figure 2. ORTEP representation of 9j; thermal ellipsoids are shown at
30% probability and hydrogen atoms are omitted for clarity.
9
8i: R’=4-MeO
8j: R’=4-Cl
8k: R’=4-F
8l: R’=5-MeO
8m: R’=6-MeO
(E)-8n: R’=3-Me
18
18
12
18
36
18
9i: 91 (90)
9j: 96 (99)
9k: 97 (99)
9l: 91 (92)
9m: 88 (71)
9n: 57 (97)
10
11
12
13
14
Scheme 2. Model for explaining the origin of asymmetric induction.
[a] Reactions were carried out on a 0.20 mmol scale using Pd(tfa)2
(5.0 mol%), ligand (7.5 mol%), and 4 ꢀ molecular sieves (80 mg) in
MeCN (2.0 mL) under O2 (1 atm; balloon) at 608C. [b] Yields of isolated
product. [c] The ee values were determined by HPLC using a chiral
stationary phase.
atom of the methoxyamine moiety in the substrate is bound to
the Pd center and is cis to the pyridine moiety of Pyrox; the
olefin moiety is bound at the position that is trans to the
pyridine moiety. When the olefin moiety of the substrate has
Z geometry, the terminal methyl group of the olefin is
oriented upward, and thus away from the tert-butyl group,
in the favored transition state. syn-Aminopalladation thus
leads to (S)-9.[21] The strongly coordinating solvent may
function as a ligand to promote both the formation and the
further transformation of the above-mentioned Pd com-
plex.[18]
obtained (Table 3, entries 2 and 3). The substrate with
isopropyl as the terminal substituent only gave the terminal
alkene product in high yield with an ee value of 94% (Table 3,
entry 4). Interestingly, the ee values of olefin products 9b’ and
9c’ were higher (up to 99%) than those of the normal aza-
Wacker-type products 9b and 9c. This difference in ee value
may be due to kinetic resolution in the isomerization step that
gives products 9b’ and 9c’, a resolution that is possible
because both the compound undergoing isomerization and
the isomerization catalyst are chiral. As the size of the
internal substituent (R group) of the olefin moiety in the
substrate increases, the enantioselectivity of the reaction
decreases slightly (Table 3, entries 1, and 5–8); however, all
products were still obtained in nearly quantitative yield. The
The OMe group could be removed by SmI2-promoted
À
reductive cleavage of the O N bond in 96% yield without
a reduction in ee value (Scheme 3). Then, introduction of
a biphenyl-2-ylmethyl group on the nitrogen atom followed
by oxidation of the olefin group and a condensation reaction
with tert-butyl amine gave 13, an analogue of drug 2, in high
overall yield with 96% ee.
In summary, we have developed an efficient catalytic
enantioselective aza-Wacker-type cyclization reaction that
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gives isoindolinones that contain a tetrasubstituted carbon
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selectivity (up to 99% yield and 99% ee).
Received: May 12, 2012
Revised: July 9, 2012
Published online: && &&, &&&&
Keywords: amination · asymmetric catalysis ·
.
aza-Wacker-type cyclization · isoindolinones ·
tetrasubstituted carbon centers
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.
Angewandte
Communications
Communications
Asymmetric Catalysis
It’s all in the solvent: An enantioselective
variant of an aza-Wacker-type cyclization
that gives isoindolinones containing tet-
rasubstituted carbon centers a to the
nitrogen atom has been developed (see
scheme; tfa=trifluoroacetate). The use
of a highly coordinating solvent is crucial
for the activity of the catalyst and the
stereoselectivity the reaction (up to
99% ee).
G. Yang, C. Shen,
W. Zhang*
&&&& — &&&&
An Asymmetric Aerobic Aza-Wacker-Type
Cyclization: Synthesis of Isoindolinones
Bearing Tetrasubstituted Carbon
Stereocenters
6
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