Enantioselective synthesis of isoindolines: An organocatalyzed domino process based on the aza-Morita-Baylis-Hillman reaction

Article abstract of DOI:10.1002/anie.201004547

Facile, selective, and organic: Acid-base organocatalyzed aza-Morita-Baylis-Hillman/aza-Michael domino reactions of α,β- unsaturated carbonyl compounds 1 with N-tosylimines 2 have been developed. The enantioselective process produces the highly functional

Full text of DOI:10.1002/anie.201004547

Angewandte
Chemie
DOI: 10.1002/anie.201004547
Organocatalysis
Enantioselective Synthesis of Isoindolines: An Organocatalyzed
Domino Process Based On the aza-Morita–Baylis–Hillman Reaction**
Shinobu Takizawa, Naohito Inoue, Shuichi Hirata, and Hiroaki Sasai*
The organocatalytic asymmetric domino process is a very
attractive method because of its ability to construct complex
chiral molecules from readily available substrates under mild
reaction conditions in two or more steps in a single operation.
These reactions can save the time and the chemicals usually
required for isolation or purification of the synthetic inter-
mediates. In addition, no concern for metal
contamination of the products is necessary
because organocatalysts do not contain
toxic or expensive metals. Examples of
organocatalytic asymmetric domino reac-
tions mediated by chiral secondary
amines[1] and hydrogen phosphates have
been recently reported;[2] these reactions
are environmentally friendly and often
proceed with excellent stereoselectivi-
ties.[3]
with a Michael acceptor moiety at the ortho position in the
presence of an organocatalyst bearing both Brønsted acid
(BA) and Lewis base (LB) units. A proposed catalytic cycle
for the aza-MBH domino reaction is shown in Scheme 1. In
the first step, the Michael addition of the Lewis base moiety to
enone 1 generates chiral enolate I stabilized by BA, it then
The aza-Morita–Baylis–Hillman (aza-
MBH) reaction is known to be a useful and
À
atom-economical C C bond-forming reac-
tion of electron-deficient alkenes with
imines and is catalyzed by Lewis bases,
such as nucleophilic amines or phos-
phines.[4] Highly functionalized allylic
amines prepared with the aza-MBH reac-
tion have proven to be valuable building
blocks for biologically active compounds
and natural products.[5] Although there are
many reports in the field of the enantiose-
lective aza-MBH processes,[6] to the best of
Scheme 1. Enantioselective aza-MBH/intramolecular aza-Michael domino reaction mediated
by an acid–base organocatalyst. Ts=4-toluenesulfonyl.
our knowledge, no report on the organo-
catalyzed domino reaction of electron-
deficient alkenes with imines has been
published.[7]
reacts with N-tosylimine 2 to form intermediate II. In the aza-
MBH reaction pathway, proton-transfer from the a position
We envisioned that chiral 1,3-disubstituted isoindoline 3
could be rapidly accessed from enone 1 and N-tosylimine 2
of the carbonyl group to the amine group and subsequent
retro-Michael reaction of the organocatalyst proceeds to form
the normal aza-MBH adduct 4. Alternatively, the nitrogen
anion of intermediate II could react with the attached
Michael acceptor intramolecularly, thus resulting in the
formation of the chiral isoindoline 3 via intermediate III
along with regeneration of the organocatalyst through
proton-transfer and subsequent retro-Michael reaction.
Optically active isoindolines are common substrates in a
variety of natural products and pharmaceutical compounds.[8]
However, research on the construction of the isoindoline core
is clearly in the early stages, and only a few methods for its
catalytic enantioselective preparation have been reported.[9]
Herein, we describe the novel organocatalyzed aza-MBH/
intramolecular aza-Michael domino reaction of a,b-unsatu-
rated carbonyl compounds with N-tosylimines to furnish 1,3-
[*] Dr. S. Takizawa, Dr. N. Inoue, S. Hirata, Prof. Dr. H. Sasai
The Institute of Scientific and Industrial Research (ISIR)
Osaka University, Mihogaoka, Ibaraki-shi
Osaka 567-0047 (Japan)
Fax: (+81)6-6879-8469
E-mail: sasai@sanken.osaka-u.ac.jp
Homepage: http://www.sanken.osaka-u.ac.jp/labs/soc/
socmain.html
[**] This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science, and
Technology (Japan). We thank the technical staff of the Compre-
hensive Analysis Center of ISIR, Osaka University.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004547.
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Communications
disubstituted isoindolines in high yields and high enantiose-
lectivities.
To explore the possibility of the proposed aza-MBH
slightly lower yield with decomposition of 2a (Table 1,
entry 4). Next, we applied known chiral acid–base organo-
catalysts, which can promote the aza-MBH reaction, for
example, b-isocupreidine (b-ICD),[6a–c] (S)-5,[6e,j] and (S)-6.[6l]
Organocatalyst b-ICD afforded 3a in poor yield with no
enantioselection together with small amounts of the aza-
MBH adduct 4a (Table 1, entry 5). Catalyst (S)-5 was found
to be inactive for the aza-MBH domino process (Table 1,
entry 6), while catalyst (S)-6 promoted the reaction to
produce 3a in low yield and ee (Table 1, entry 7). To our
domino process, we began with the reaction of methyl vinyl
ketone (1a; 3.0 equiv) and N-tosylimine 2a in CHCl3 at room
temperature in the presence of organocatalysts (10 mol%;
Table 1). 1,4-Diazabicyclo[2.2.2]octane (DABCO), 4-(dime-
thylamino)pyridine (DMAP), and PPh3 as achiral Lewis bases
catalyzed the reaction to afford only the desired isoindoline
3a in moderate yields (64–73%; Table 1, entries 1–3). The
reaction mediated by mixing PPh3 (10 mol%) and (S)-binol
(10 mol%) as the chiral Brønsted acid, formed racemic 3a in
delight,
we
found
that
(S)-2-diphenylphosphanyl-
[1,1’]binaphthalenyl-2-ol ((S)-7),[10] an acid–base organocata-
lyst developed by Shi et al.,[6d,f] mediated the reaction
efficiently to afford 3a in moderate yield with high enantio-
selectivity (Table 1, entry 8). The H8-binol derivative (S)-8,[11]
which has a larger dihedral angle than (S)-7, showed little
improvement on the asymmetric induction (Table 1, entry 9).
The catalytic activity was remarkably decreased with catalyst
(S)-9,[6f] which has a phenyl group at the 3’-position (Table 1,
entry 10). Activity was also low with catalysts (S)-5 and (S)-6,
owing to the steric bulkiness, thus resulting in the formation of
aza-MBH adduct 4a as the major product (Table 1, entries 6
and 7). Chiral phosphines as the sole Lewis base catalysts for
example, (S)-binap and (R)-mop,[10] drastically decreased
yields and ee values of 3a and were accompanied by
pronounced decomposition of 2a (Table 1, entries 11 and
12). These outcomes indicate that the introduction of acid–
base units at the appropriate positions on a single chiral
skeleton assists in effectively promoting the aza-MBH
domino reaction with high enantiocontrol. Notably, product
3a was obtained as a single diastereomer for all entries. cis-
1,3-Disubstited isoindoline is known to be thermodynamically
more stable than the trans form.[12] Because the intramolec-
ular aza-Michael process would be reversible, cis-3a could be
formed as a single diastereomer (DE = 4.13 kcalmolÀ1 based
on MM2 calculations).
Table 1: Enantioselective aza-MBH domino reaction of 1a with 2a.[a]
Entry
Catalyst
3a
4a
Yield [%][b]
ee [%][c]
Yield [%][b]
ee [%][c]
1
2
3
DABCO
DMAP
PPh3
PPh3
b-ICD
(S)-5
(S)-6
(S)-7
(S)-8
(S)-9
69
64
73
59
15
trace
14
62
58
12
13
27
–
–
–
0
0
0
–
–
–
–
4[d]
5
racemate
racemate
n.d.
19 (R,S)
87 (R,S)
84 (R,S)
82 (R,S)
racemate
14 (R,S)
0
13
56
36
0
0
36
0
n.d.
48 (R)
racemate
–
6
7
8
9
10
11
12
–
82 (R)
–
–
(S)-binap
(R)-mop
0
[a] Reaction conditions: 1a (0.15 mmol), 2a (0.050 mmol), catalyst
(10 mol%), 0.25m (concentration of 2a) in CHCl3, room temperature.
[b] Yields were determined from the 1H NMR spectra using benzyl phenyl
ether as an internal standard. [c] Determined by HPLC analysis on a
chiral stationary phase using a Daicel Chiralpak IA column. [d] In the
presence of (S)-binol (10 mol%). binol=1,1’-bi-2-naphthyl, n.d.=not
determined.
The optimal result (98% yield, 92% ee) was obtained
[13]
when the reaction of 1a with 2a was performed in CHCl3
(0.2m for 2) at 108C in the presence of molecular sieves (M.S.;
3 ꢀ)[14] as an additive (Table 2, entry 1). Ethyl vinyl ketone
(1b) and phenyl vinyl ketone (1c) were also suitable
substrates and led to isoindolines 3b and 3c, respectively,
with high ee values (Table 2, entries 2 and 3). Other a,b-
unsaturated carbonyl compounds, for example, acrolein (1d)
and phenyl acrylate (1e), promoted reactions with acceptable
results (Table 2, entries 4 and 5). When the substituent R3 on
N-tosylimines 2 was changed, isoindolines 3 f and 3g were
formed in good yields (Table 2, entries 6 and 7). High
enantioselectivities (Table 2, 89–93% ee) were obtained irre-
spective of the electronic nature of substituent groups at the
5-position on the aromatic ring of 2 (Table 2, entries 8–10).
Substituent groups at the 6- and 3-positions led to 3k and 3m
with 82 and 85% ee, respectively (Table 2, entries 11–13).
The relative and absolute configurations of the isoindoline
3b was determined by NMR spectroscopy and X-ray crys-
tallographic analysis.[15] The aza-MBH/intramolecular aza-
Michael domino reaction was found to be cis selective and
(R,S)-configured isoindolines 3 were formed (Figure 1).
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Table 2: Scope of aza-MBH domino reaction catalyzed by (S)-7.[a]
To provide mechanistic insight into this domino reaction,
we performed the intramolecular aza-Michael reaction of
racemic aza-MBH adduct 4a catalyzed by (S)-7 in CHCl3 at
À208C. The reaction was very slow and only trace amounts of
isoindoline 3a were formed along with recovery of most of 4a
[Eq. (1)]. Under the same conditions, the domino reaction of
Entry R1
N-Tosylimine
Yield
[%][b]
ee
[%][c]
R2, R3
1[d]
2[d]
3[d]
4[d]
5[d]
6
Me (1a)
H, Me
H, Me
H, Me
H, Me
2a 98 (3a)
2a 97 (3b)
2a 72 (3c)
2a 49 (3d)
2a 66 (3e)
2b 85 (3 f)
2c 78 (3g)
2d 75 (3h)
2e 80 (3i)
2 f 76 (3j)
2g 88 (3k)
92
92
88
87
68
93
91
89
92
93
82
Et (1b)
Ph (1c)
H (1d)
enone 1a with N-tosylimine 2a led to 3a in 38% yield with
94% ee without formation of 4a [Eq. (2)]. Judging from these
experimental results, it is apparent that intramolecular
OPh (1e) H, Me
1a
1a
1a
1a
1a
1a
H, Et
H, Bn
5-Me, Me
5-F, Me
5-Cl, Me
6-Cl, Me
7
8[d]
9
10[e]
11[d]
12
1a
2h
82
cyclization of aza-MBH intermediate II produces isoindoline
3 directly without forming aza-MBH adduct 4a (Scheme 1).
To demonstrate the synthetic utility of the highly func-
tionalized aza-MBH domino product 3a, a variety of trans-
formations were performed (Scheme 2). The allyl alcohol 10
73 (3l)
13[d]
1a
2i
85
88 (3m)
[a] Reaction conditions: 1 (0.10 mmol), 2 (0.050 mmol), catalyst (S)-7
(10 mol%), 0.2m (concentration of 2) in CHCl3, 108C. [b] Yield of
isolated product. [c] Determined by HPLC on a chiral stationary phase
(Daicel Chiralpak IA for 3a–d, 3 f–j, and 3l,m; Daicel Chiralpak IB for 3e;
Daicel Chiralpak IC for 3k). [d] 3 ꢀ M.S. was used as an additive. [e] 4 ꢀ
M.S. was used as an additive. M.S.=molecular sieves.
Scheme 2. Synthetic transformations of isoindoline (R,S)-3a. Reagents
and conditions: a) Yb(OTf)3 (1.5 equiv), NaBH4 (1.5 equiv), MeOH,
THF, 08C, 30 min, 88% (d.r.=77:23, determined by 1H NMR spectros-
copy); b) Mg (20 equiv), MeOH, RT, 2 h, 98%; c) Zn (20 equiv), aq
NH4Cl, THF, RT, 12 h, 73% (d.r.>99:1, determined by HPLC analysis);
d) dibenzyl malonate (1.2 equiv), DBU (1.2 equiv), THF, À408C, 72 h,
90% (d.r.=96:4, determined by HPLC analysis); e) LiOH (5.0 equiv)
in aq., THF, RT, 26 h, 90%. Bn=benzyl, DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene, Tf=trifluoromethanesulfonyl, THF=tetrahydro-
furan.
Figure 1. X-ray structure of the isoindoline (R,S)-3b. The hydrogen
atoms are omitted for clarity. Thermal ellipsoids are drawn at 50%
probability.
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Communications
[5] For recent reviews on the aza-Morita–Baylis–Hillman reaction,
see: a) G. Masson, C. Housseman, J. Zhu, Angew. Chem. 2007,
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could be formed by Luche reduction of 3a in the presence of
Yb(OTf)3.[16] Treatment of the major diastereomer 10 with
Mg/MeOH[17] cleaved the Ts group to provide the amino
alcohol 11 in 98% yield. The a-methyl ketone 12 was also
obtained in good yield as a single diastereomer by 1,4-
conjugate reduction of 3a using Zn powder/NH4Cl, without
overreduction. Furthermore, the Michael addition of dibenzyl
malonate to 3a with DBU produced the adduct 13 in 90%
yield with high diastereoselectivity (d.r. = 96:4). Finally, 3a
was easily hydrolyzed to b-amino acid 14 by exposure to
aqueous LiOH/THF, and high enantiopurity was maintained.
In summary, we have developed the first enantioselective
aza-MBH/intramolecular aza-Michael reaction of electron-
deficient alkenes and N-tosylimines promoted by a chiral
acid–base organocatalyst. The aza-MBH domino process
described here was easily accessed to afford 1,3-disubstituted
isoindolines in good yields with excellent diastereo- and
enantioselectivities (up to 93% ee). The obtained product was
transformed reliably into a variety of derivatives. Further
investigations to extend the reaction scope and illustrate
applications of this process in organic synthesis are underway.
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Experimental Section
General procedure: Enone (0.10 mmol, 2.0 equiv) was added to a
solution of organocatalyst (S)-7 (10 mol%), N-tosylimine
(0.050 mmol), and powdered M.S. (3 ꢀ or 4 ꢀ; 10 mg) in CHCl3
(0.25 mL). The reaction mixture was stirred at 108C for 72 h. The
solvent was evaporated under reduced pressure and the crude
product was purified by flash chromatography on silica gel (n-
hexane/EtOAc = 4:1) to afford the isoindoline product.
Received: July 24, 2010
Revised: September 6, 2010
Published online: November 9, 2010
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Keywords: asymmetric catalysis · aza-Michael addition ·
domino reactions · isoindolines · organocatalysis
.
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[14] The addition of M.S. (3 ꢀ or 4 ꢀ) was beneficial to suppress the
decomposition of moisture sensitive N-tosylimines 2 (see the
Supporting Information).
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