Catalytic Enantioselective Synthesis of Mariline A and Related Isoindolinones through a Biomimetic Approach

Article abstract of DOI:10.1002/anie.201709182

The catalytic enantioselective synthesis of isoindolinones was achieved through the condensation of 2-acyl-benzaldehydes and anilines. In the presence of 1 mol % of a chiral phosphoric acid catalyst, reactions reach completion within 10 min and provide products with up to 98 % ee. Anilines with an ortho t-butyl group form atropisomeric products, thereby enabling the simultaneous generation of axial and point chirality from two achiral substrates. This method was applied to the first synthesis of mariline A.

Full text of DOI:10.1002/anie.201709182

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Accepted Article
Title: Catalytic Enantioselective Synthesis of Mariline A and Related
Isoindolinones via a Biomimetic Approach
Authors: Chang Min, Yingfu Lin, and Daniel Seidel
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201709182
Angew. Chem. 10.1002/ange.201709182
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10.1002/anie.201709182
Angewandte Chemie International Edition
COMMUNICATION
Catalytic Enantioselective Synthesis of Mariline A and Related
Isoindolinones via a Biomimetic Approach
Chang Min,+,[a] Yingfu Lin,+,†,[a] and Daniel Seidel*,†,[a]
Abstract: The catalytic enantioselective synthesis of isoindolinones
was achieved via the condensation of ortho-formyl-arylketones and
anilines. In the presence of 1 mol% of a chiral phosphoric acid
catalyst, reactions reach completion within 10 minutes and provide
products with up to 98% ee. Anilines with an ortho t-butyl group form
atropisomeric products, enabling the simultaneous generation of axial
and point chirality from two achiral substrates. This method was
applied to the first synthesis of mariline A.
enantiodetermining step is the tautomerization of 3 to ultimately
provide 4. While not generating a new stereogenic center, the
same mechanism is generally thought to be operative in the
closely related and well known condensation of amines with
ortho-phthaldialdehydes,[12] although alternative mechanistic
pathways have also been proposed.[13] König, Bringmann and
coworkers, who isolated (±)-mariline A and similar natural
products, proposed that this type of condensation reaction might
in fact represent the biosynthetic pathway to these and other
isoindolinones.[1] Schmalz et al. later provided further credence
to this proposal by preparing a close analogue of (±)-mariline A
Isoindolinones are important pharmacophores and form the core
of
a
range of natural products such as mariline A,[1]
from
appropriate
amine
and
ortho-formyl-arylketone
lennoxamine[2] and pestalochloride A[3] (Figure 1).[4] Largely due
to their manifold biological activities, there has been a long-
standing interest in the asymmetric synthesis of chiral
isoindolinones.[4] However, catalytic enantioselective methods
remain underdeveloped. Previous approaches have focused on
constructing the lactam moiety via 1,2-addition of nucleophiles to
ortho-formyl-benzoate-derived imines, with subsequent amide
precursors.[11b] It is of interest to note that mariline A and
analogues as well as pestalachloride A were isolated from their
natural sources in their racemic forms.
However,
enantiomerically pure mariline
configurationally stable.[1]
A
was shown to be
bond forming ring closure.[5]
Intramolecular additions of
benzamides to ortho-olefins, including conjugate additions[6] and
an asymmetric aza-Wacker-type cyclization[7] have also been
disclosed. Other approaches are known, including the catalytic
enantioselective reduction or addition to lactam hemiaminals (not
shown).[8]
A
particularly attractive approach to chiral
isoindolinones was recently reported by Schmalz and coworkers
who showed that the marine antibiotic pestalone[9] undergoes
facile conversion to (±)-pestalachloride A upon exposure to
ammonia/ammonium chloride in aqueous dioxane (Figure 1).[10]
The same group later showed that this type of reaction is general
for a range of amines and ortho-formyl-arylketones.[11] Here we
report the first catalytic enantioselective version of this valuable
transformation.
The proposed mechanism for the formation of isoindolinones
from ortho-formyl-arylketones 1 and amines involves the initial
formation of cyclic bis-hemiaminal 2, followed by loss of water to
give hydroxy-isoindoline intermediate 3.[11a]
The key
[a]
Dr. C. Min, Y. Lin, Prof. Dr. D. Seidel
Department of Chemistry and Chemical Biology
Rutgers, The State University of New Jersey
Piscataway, NJ 08854 (USA)
Figure 1. Selected isoindolinone natural products, previous enantioselective
approaches, and a potentially biosynthetic pathway to this heterocycle.
E-mail: seidel@chem.ufl.edu
Homepage: http://seidel-group.com/
These authors contributed equally to this work.
Present address:
Department of Chemistry
University of Florida
+
†
We were intrigued by the prospect of developing a catalytic
enantioselective variant of this biomimetic condensation
reaction.[14] Although the optimized conditions developed by
Schmalz et al. involve the use of excess acetic acid in a polar
reaction medium, we reasoned that a catalytic amount of a chiral
Brønsted acid should suffice to facilitate the key protonation
step.[15–17] Considering that the final product is relatively non-
basic, product inhibition of the catalytic cycle was not expected to
Gainesville, Florida 32611 (USA)
This material is based upon work supported by the National Science
Foundation under CHE – 1565599. We thank Dr. Tom Emge
(Rutgers University) for crystallographic analysis.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201709182
Angewandte Chemie International Edition
COMMUNICATION
represent a significant problem. To validate this proposal, ortho-
formyl-arylketone 1a was tested in combination with various
amine-type substrates in the presence of chiral phosphoric acid
catalyst (S)-TRIP[18] (Table 1). Benzyl carbamate (entry 1) and
tert-butylamine (entry 2) were unreactive under a range of
conditions. Other amines underwent rapid reactions with 1a. Full
conversion of 1a occurred in less than 10 min in all cases.
Prolonged reaction times had no effect on the yields or ee’s of the
substrate concentration (10 and 11) provided no obvious further
improvements.
Table 2. Optimization of Reaction Parameters.a
desired isoindolinones 4.
In accord with Schmalz’s
observations,[11] highly polar polymer-like byproducts are formed
in competing side reactions and the outcome of a particular
reaction strongly depends on the nature of the amine. Benzyl
amine provided product 4c in moderate yield and low ee (entry 3).
Whereas nearly no product 4d could be detected with parent
aniline, again in agreement with findings by the Schmalz group
(entry 4),[11] p-methoxy aniline provided isoindolinone 4e in
moderate yield albeit racemic form (entry 5). Other electron-rich
anilines afforded products in moderate to good yields but with
entry
temp
[°C]
(S)-TRIP
(mol%)
concentration
[M]
yield
(%)
ee
(%)
1
2[b]
rt
rt
10
10
10
10
1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.05
71
54
75
65
71
72
55
74
61
74
68
83
49
97
93
97
97
92
97
94
96
97
3
0
4
‒20
0
5
6[c]
0
1
7
0
0.1
1
8[d]
9[e]
10
11
0
typically low ee’s (entries 6–10).
enantioselectivity was observed with 2-OtBu aniline, allowing for
the isolation of product 4k in 71% yield and 83% ee (entry 11).
A dramatic increase in
0
1
0
1
0
1
[a]
Table 1. Initial Evaluation of Amine Component.a
Yields are those of chromatographically purified compounds. The ee values
were determined by HPLC analysis; see the Supporting Information for details.
[b]
[c]
[d]
In the presence of 4Å MS.
5 equiv of water were added.
4 equiv of 2-
OtBu aniline were used. [e] 1.2 equiv of 2-OtBu aniline were used.
entry
R
Cbz
product
4a
yield (%)
NR
NR
44
ee (%)
1
2
-
tBu
4b
4c
-
3
Bn
13
-
4
Ph
4d
4e
trace
54
5
4-MeO-C6H4
2-MeO-C6H4
2,4-OMe2C6H3
2,6-OMe2C6H3
2,6-Me2C6H3
3,4,5-(OMe)3C6H2
2-OtBuC6H4
0
6
4f
49
10
49
65
11
19
83
7
4g
4h
4i
66
8
67
9
88
10
4j
70
11
4k
71
[a]
Yields are those of chromatographically purified compounds. The ee values
were determined by HPLC analysis; see the Supporting Information for details.
NR: no reaction
Utilizing 2-OtBu aniline, other reaction parameters were
evaluated next (Table 2).
Interestingly, while the reaction
generates water as a byproduct, the addition of molecular sieves
resulted in a dramatic decrease in the yield and ee of 4k (entry 2),
indicating an important role for water in the overall process.[19,20]
A reduction of the reaction temperature to 0 °C brought about a
significant increase in ee without apparent effect on the rate of
the reaction (entry 3).
However, further decreasing the
temperature to ‒20 °C caused a drop in both yield and ee (entry
4). The catalyst loading could be reduced to 1 mol% without
adverse effects (entry 5). The reaction was insensitive to
moisture; the addition of water had no effect on the results (entry
6). A reduction in catalyst loading to 0.1 mol% still provided
product 4k in excellent ee, albeit in lower yield (entry 7).
Variation of the amount of 2-OtBu aniline (entry 8 and 9) or the
Scheme 1. Substrate Scope.
The scope of the isoindolinone formation was explored with a
range of ortho-formyl-arylketones and primary aromatic amines
(Scheme 1). A number of 2-OtBu anilines bearing additional ring-
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10.1002/anie.201709182
Angewandte Chemie International Edition
COMMUNICATION
substituents provided products in moderate to good yields and
excellent enantioselectivities. 2-OTIPS-aniline underwent the title
reaction to form product 40 in excellent ee whereas the use of 2-
phenoxyaniline resulted in product 4p with reduced ee albeit
atropisomer 5a was readily obtainable in pure form via column
chromatography. A solution of 5a that was kept at room
temperature for several days showed no sign of 5aʹ. Presumably
due to lower rotational barriers, atropisomers were not observable
for products 4 (Scheme 1).[24] The preferred conformation of
increased yield.
Mono-N-Boc ortho-phenylenediamine also
underwent the transformation to form isoindolinone 4q in good
yield and ee. As for the ortho-formyl-arylketone component, both
electron-donating and electron-withdrawing groups on different
ring positions were tolerated, generating isoindolinone products in
moderate to good yields and excellent levels of enantioselectivity.
Change of the 3-methyl group to ethyl or benzyl was tolerated but
led to a slight reduction in enantioselectivity.
products 4 likely corresponds to that of 5.
In fact, this
conformation was observed in the X-ray crystal structure of 4s,
which also served to establish its absolute configuration.[25]
As shown in eq 1, removal of the t-butyl group in 4k was
readily achieved upon treatment with phosphoric acid, allowing
for the isolation of product 6 in excellent yield. Importantly, the ee
was unaffected by this transformation.
The title reaction was applied in a relatively straightforward
synthesis of mariline A, starting from commercially available
benzoic acid derivative 7 (Scheme 3). Key steps include the
monobromination of ketone 8 to provide 9 and subsequent
regioselective monomethylation to yield intermediate 10. The key
catalytic enantioselective step proceeded in 93% ee.[26]
In summary, we have achieved the catalytic enantioselective
synthesis of 3-alkyl isoindolinones via a biomimetic condensation
approach, utilizing ortho-formyl-arylketones and 2-substituted
anilines as starting materials. This method enabled the first
enantioselective synthesis of mariline A.
Scheme 2. Formation of Atropisomeric Products.
Interestingly, with 2-tBu aniline as the amine component, we
observed the formation of diastereomeric products (Scheme 2).
Specifically, the two atropisomers 5a and 5aʹ were obtained in a
7.5:1 ratio, both with nearly identical ee (93/92%).[21–23] Similar
results were obtained for 2-tBu-4-chloroaniline and 2-tBu-4-
bromoaniline. A reaction of 1a and 2-tBu aniline, performed at
room temperature and monitored by 1H-NMR, revealed that 5aʹ is
the kinetic product which appears to be formed exclusively in the
initial stages of the reaction. By the time the reaction reached
completion, the ratio of 5a and 5aʹ was found to be 1:9. Over the
course of two days this ratio changed to 7:1. Purification of a
reaction mixture by column chromatography immediately after
consumption of 1a led to a rapid change of the atropisomeric
composition corresponding to the reported values. The major
Keywords: asymmetric organocatalysis • Brønsted acid
catalysis• mariline A • atropisomerism • isoindolinones
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Scheme 3. Enantioselective synthesis of mariline A.
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[24] König and Bringmann et al. recognized the potential role of axial
chirality in mariline A. Rotational barriers were calculated to be 11.6
and 14.4 kcal mol–1, respectively, indicating free rotation around the
N,C axis. The atropisomer of mariline A corresponding to 5 was
calculated to be 2.81 kcal mol–1 lower in energy than the atropisomer
corresponding to 5aʹ. See reference 1.
[25] See the Supporting Information.
[26] Based on analogy to product 4s, the absolute configuration of mariline
A was assigned as (R). See the Supporting Information for further
discussion.
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Entry for the Table of Contents
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Chang Min, Yingfu Lin, and Daniel
Seidel*
Page No. – Page No.
Catalytic Enantioselective Synthesis
of Mariline A and Related
Isoindolinones via a Biomimetic
Approach
The catalytic enantioselective synthesis of isoindolinones was achieved via the
condensation of ortho-formyl-arylketones and anilines. In the presence of 1 mol%
of a chiral phosphoric acid catalyst, reactions reach completion within 10 minutes
and provide products with up to 98% ee. Anilines with an ortho t-butyl group form
atropisomeric products, enabling the simultaneous generation of axial and point
chirality from two achiral substrates. This method was applied to the first synthesis
of mariline A.
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