Organocatalytic Michael addition of malonates to isatylidene-3- acetaldehydes: Application to the total synthesis of (-)-debromoflustramine e

Article abstract of DOI:10.1002/chem.201300977

Flustering oxindoles: An enantioselective synthesis of 3,3′- disubstituted oxindoles by conjugate addition of malonates to isatylidene-3-acetaldehydes in high yield and enantioselectivity is developed (see scheme). The synthetic utility of this reaction i

Full text of DOI:10.1002/chem.201300977

COMMUNICATION
DOI: 10.1002/chem.201300977
Organocatalytic Michael Addition of Malonates to Isatylidene-3-
acetaldehydes: Application to the Total Synthesis of
(À)-Debromo
ACHTUNGTRENfNUNG lustramine E
Renrong Liu[a] and Junliang Zhang*[a, b]
Oxindoles bearing a quaternary carbon stereocenter at
the 3-position are ubiquitous in nature and have been
shown to be valuable building blocks for alkaloid synthe-
sis.[1] Several strategies have been developed to achieve the
enantioselective synthesis of 3,3’-disubstituted oxindoles, in-
cluding 1) the direct functionalization of 3-substituted oxin-
doles;[2] 2) intramolecular coupling reactions (Heck[3] and
arylation reactions[4]); 3) the rearrangement of indolyl ace-
tates and carbonates;[5] and 4) the alkylation of 3-halooxin-
doles or 3-hydroxyoxindoles.[6]
In recent years, methyleneindolinones have attracted con-
siderable attention as novel substrates for the enantioselec-
tive synthesis of 3,3’-dialkyloxindoles.[7] Trost and co-work-
ACHTUNGTRENNUNG
ers[7a] first reported an enantioselective palladium-catalyzed
[3+2] cycloaddition reaction of 3-alkylideneoxindolin-2-ones
with cyano-substituted trimethylenemethane to construct
spirocyclic oxindolic cyclopentanes. The groups of Melchior-
re,[7b] Barbas,[7c–e] Gong,[7f] Chen,[7g] Bencivenni,[7h] and
Wang[7i,j] have developed several excellent organocatalytic
methods to construct spirooxindoles by using methylenein-
dolinones in tandem reactions. Waldmann and co-workers[8]
also developed a highly enantioselective Lewis acid cata-
lyzed 1,3-dipolar cycloaddition reaction for the synthesis of
3,3’-pyrrolidinylspirooxindoles. However, all of these meth-
ods were initiated by a nucleophilic addition at the b-posi-
tion, leading to b-adducts (type A, Scheme 1a) and the qua-
ternary stereogenic centers were constructed in the second
step by intramolecular functionalization of 3-substituted ox-
indoles. These methods are limited to cyclic quaternary ster-
eogenic centers.
Scheme 1. Previous and proposed work.
In 1980, Kimio and co-workers[9a] reported a tandem reac-
tion of 1,3-diones and isatylidene malononitriles to afford
spirooxindoles, initiated by a conjugated addition at the a-
position (Scheme 1b). However, recently, Yuan and co-
workers[9b] reported the first enantioselective method for the
synthesis of spiro[4H-pyran-3,3’-oxindole] derivatives in a
reaction catalyzed by cupreine. Shortly after this, Wang,
Tao, and co-workers[9c] reported an efficient construction of
the spirooxindole backbone in an optically pure form
through a cascade Michael addition of isatylidene malononi-
triles with unsaturated ketones. Lu and co-workers[9d] also
reported an elegant phosphine-catalyzed asymmentric [3+2]
cycloaddition reaction of Morita–Baylis–Hillman adducts
with isatylidene malononitriles leading to 3-spirocyclopen-
tene-2-oxindoles. Recently, Wang and co-workers[9e,f] dis-
closed two organocatalytic, highly enantioselective conjugat-
ed addition reactions of ketones or nitroalkanes to isatyli-
dine malononitriles and indolylidenecyanoacetates, leading
to optically active a adducts. However, to synthesize these a
adducts with a chiral quaternary stereocenter, these methods
(Scheme 1b) require two electron-withdrawing groups, one
of which must be a nitrile group,[10] limiting their use. Very
recently, Arai and co-workers developed an elegant method
to construct 3,3’-disubstituted oxindoles that is catalyzed by
[a] R. Liu, Prof. Dr. J. Zhang
Shanghai Key Laboratory of Green Chemistry and
Chemical Processes, Department of Chemistry
East China Normal University
3663 N. Zhongshan Road, Shanghai 200062 (P.R. China)
Fax : (+86)21-6223-3213
E-mail: jlzhang@chem.ecnu.edu.cn
[b] Prof. Dr. J. Zhang
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032 (P.R. China)
CuACTHNUGTRENNG(U OTf)2 using isatin-derived nitroalkenes as a novel meth-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300977.
yleneindolinone.[11]
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Table 1. Catalyst screening and optimization of the reaction conditions.[a]
Iminium catalysis has now been established as one of the
key catalytic concepts in organocatalysis.[12] We envisioned
that isatylidene-3-acetaldehyde (Scheme 1c), the electrophil-
ic position in which may convert from b to a through imini-
um catalysis by use of LUMO-lowering activation, may be a
good candidate to construct the quaternary carbon stereo-
center. However, asymmetric conjugate addition to a b,b-
disubstituted a,b-unsaturated aldehyde is still a very chal-
lenging task.[13] We report herein a new enantioselective syn-
thesis of 3,3’-disubstituted oxindoles by conjugate addition
of malonates to isatylidene-3-acetaldehyde under iminium
catalysis. This transformation provides a facile route for the
enantioselective total synthesis of debromoflustramine E. To
the best of our knowledge, this is the first example of the
use of b-carbonyl-substituted a,b-unsaturated aldehydes to
construct the quaternary stereocenter.[14–16]
In our initial study, we found, to our delight, that in the
presence of catalyst 3a and PhCO2H, the Michael addition
of dimethyl malonate 2a to isatylidene-3-acetaldehyde ((E)-
1a) gave the desired product 4a with moderate enantiose-
lectivity (Table 1, entry 1). Gratifyingly, the Z isomer of 1a
gave a higher enantioselectivity (Table 1, entry 2). A variety
of a,a-diaryl prolinol derived catalysts were screened
(Figure 1). With catalyst 3c, we could obtain higher enantio-
Entry
Catalyst
Additive
t
Yield 4a
ee
[h]
[%]
[%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18[f]
19[g]
20[h]
21[i]
22[j]
3a
3a
3b
3c
3d
3e
3 f
3g
3h
3i
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
2-F-PhCO2H
NaOAc
3
3
3
3
3
3
3
3
3
3
3
3
3
1
0.5
0.5
0.5
72
75
65
30
81
50
45
35
–
62
65
78
70
80
–
50[b]
66
84
91[c]
88
46
41
66
[d]
–
50
67
78
67
79
3j
3k
3l
3d
3d
3d
3d
3d
3d
3d
3d
3d
[d]
–
TsOH
TFA
0 (75)[e]
0 (80)[e]
81
81
81
78
72
–
–
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
24
48
24
84
176
90
93
93
92
92
Figure 1. Screened catalysts (TMS=trimethylsilyl, TIPS=triisopropyldil-
yl, TES=triethylsilyl TBS=tert-butyldimethylsilyl,Naph=naphthyl).
[a] Reaction conditions: 1a (0.06 mmol, 1.0 equiv), 2a (0.12 mmol,
2.0 equiv), catalyst (20 mol%), PhCO2H (20 mol%), H2O (1.3 equiv)
with the solvent indicated (0.1m) at room temperature. [b] (E)-1a was
used. [c] Compound 6 was formed as the major product. [d] Complex
mixture of products. [e] The number in parentheses refers to the isolated
yield of compound 5. [f] The reaction was performed at 08C. [g] The re-
action was performed at À208C. [h] The reaction was performed with
H2O (1.3 equiv) at À208C. [i] The reaction was performed with the cata-
lyst (10 mol%) and H2O (1.3 equiv) at À208C. [j] The reaction was per-
formed with the catalyst (5 mol%) and H2O (1.3 equiv) at À208C.
selectivity, but in only 30% yield, and a significant amount
of the condensation product
6 was isolated (Table 1,
entry 4). To our delight, the reaction proceeded smoothly to
afford the desired product in 81% yield and 88% enantio-
meric excess (ee) at room temperature when the TBS-pro-
tected compound 3d was employed as the catalyst (Table 1,
entry 5). Unfortunately, no improvement in enantioselectivi-
ty was achieved by use of the other catalysts screened,
which contain a variety of silyl ether (3e–3g), phenyl, and
aryl groups (3h–3j and 3k–3l; Table 1, entries 6-13). When
a stronger acid was used, none of the desired product was
formed. The acetal product 5 was obtained from reactions in
EtOH (Table 1, entries 16 and 17). Further screening of the
reaction conditions revealed that lowering the temperature
to 08C resulted in a slightly better enantioselectivity of
90% ee (Table 1, entry 18), and up to 93% ee could be
achieved by lowing the temperature to À208C (Table 1,
entry 19). Indeed, the addition of 1.3 equivalents of water
accelerated the reaction rate without loss of enantioselectiv-
ity (Table 1, entry 20). To our delight, reducing the catalyst
loading did not alter the enantioselectivity or the efficiency
too much, requiring only a longer reaction time (Table 1, en-
tries 21–22).
With the optimal reaction conditions in hand, we investi-
gated the reaction scope by varying two reaction compo-
nents. Generally, both electron-withdrawing and -donating
substituents on the oxindole moiety were tolerated, afford-
ing the corresponding products with ꢀ90% ee (Table 2, en-
tries 1–11). The reaction of 4-Br substituted 1g offered the
highest enantioselectivity (99% ee) and yield (91%; Table 2,
entry 7). In general, the substrates containing electron-with-
drawing groups gave lower yields and enantiomeric excesses
than those containing electron-donating groups, which may
be due to the fact that these substrates are highly reactive
and easily undergo side reactions. The substituent effect of
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Michael Addition of Malonates
COMMUNICATION
Table 2. Substrate scope of isatylidene-3-acetaldehyde and malonate.[a]
Entry
R/R1 (1)
R2 (2)
t
Yield (4)
ee
[d]
[%][b]
[%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
H/Bn (1a)
5-Me/Bn (1b)
5-OMe/Bn (1c)
5-Br/Bn (1d)
5-Cl/Bn (1e)
5-F/Bn (1 f)
4-Br/Bn (1g)
6-Br/Bn (1h)
7-Me/Bn (1i)
7-Cl/Bn (1j)
7-F/Bn (1k)
H/Me (1l)
H/allyl (1m)
H/prenyl (1n)
H/Ph (1o)
H/H (1p)
Me (2a)
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
1.5
2
2.5
2
81 (4a)
83 (4b)
80 (4c)
71 (4d)
70 (4e)
60 (4 f)
91 (4g)
70 (4h)
73 (4i)
70 (4j)
63 (4k)
73 (4l)
67 (4m)
61 (4n)
70 (4o)
82 (4p)
82 (4q)
83 (4r)
83 (4s)
81 (4t)
88 (4u)
82 (4v)
93
94
96
95
92
90
99
94
96
98
93
88
90
91
90
80
91
97
97
95
93
93
1
1.5
1.5
3
2
2
2
1.5
1.5
1.5
1
2
Scheme 2. The total synthesis of (À)-debromoflustramine E. Reaction
conditions: a) 2a (2.0 equiv), 3d (10 mol%), PhCO2H (20 mol%), H2O
(1.3 equiv), EtOH, À208C; b) nBuLi, Ph3P+CHMe2IÀ, THF, 08C;
5-Me/allyl (1q)
5-OMe/allyl (1r)
1r
1a
1a
1.5
1.5
1.5
1.5
1.5
2.5
2a
Bn (2b)
2b
allyl (2c)
Et (2d)
c) NaCl, DMSO/H2O, 1608C; d) MeNH2ACTHUNRTGNEUNG(EtOH), 608C; e) LiAlH4, THF,
08C; f) LiAlH4, THF, reflux; g) Na/NH3(l), À788C (Bn=benzyl).
1a
methyl amide 9, which was then reduced with LiAlH4 over
two steps, first at 08C and then at reflux, to yield compound
11. Under the Na/NH3 conditions, deprotection of the
benzyl group easily took place to afford (À)-debromoflus-
tramine E (12) in 90% yield (7 steps, 29% overall yield
[a] Reaction conditions: 1a (0.25 mmol, 1.0 equiv), 2a (0.5 mmol,
2.0 equiv), catalyst 3d (20 mol%), PhCO2H (20 mol%), H2O (1.3 equiv)
with EtOH (0.1m) at À208C. [b] Yield of the isolated product. [c] Deter-
mined by HPLC analysis on a chiral stationary phase.
N-protecting groups on the oxindole moiety was also investi-
gated (Table 2, entries 12–15) and it was found that not only
alkyl groups, such as methyl, allyl, and prenyl, but also aryl
groups were compatible, efficiently yielding the desired
products in high enantioselectivity. The N-unprotected com-
pound 1p could provide product 4p in 82% yield but slight-
ly lower ee (80%; Table 2, entry 16). Next, diethyl, dibenzyl,
and diallyl malonates 2b–2d were investigated and all of
these malonates were applicable in this transformation,
giving 81–88% yields of the products in 93–97% ee
(Table 2, entries 19–22).
from
isatylidene-3-acetalde-
hyde, 1a). The absolute config-
uration was determined by
comparison of the optical rota-
tion with that reported in the
literature.[18e,j] This absolute
configuration is reasonable con-
sidering that the malonate com-
ponent approaches opposite the
face of the bulky diphenyl(tert-
butyldimethylsiloxy)methyl
Figure 2. The transition state
of the reaction.
Pyrrolidinoindolines bearing a prenyl substitutent at C3 of
group (Figure 2).
the hexahydropyrrolo
[2,3-b]indole ring system have been
As well as hexahydropyrrolo
ACHTUNGTRNE[NUNG 2,3-b]indoles, the spirooxin-
obtained from a diverse array of natural sources.[17] The effi-
cient and enantioselective construction of the prenyl-substi-
tuted quaternary carbon center at the C3 position offers an
interesting synthetic problem.[18] The utility of the conjugate
addition of malonates to isatylidene-3-acetaldehyde is dem-
onstrated by a total synthesis of (À)-debromoflustramine E
(Scheme 2). The enantioselective Michael addition gave 4a
in 80% yield and 90% ee, running with 1.0 g of 1a and
10 mol% catalyst 3d. The Wittig reaction of 4a furnished
compound 7 in 72% yield, which was subjected to Krapcho
decarboxylation to give the desired product 8 in 92% yield.
The amidation reaction of 8 with methylamine produced the
dole and hexahydrofurano[2,3-b]indole cores also frequently
ACHTUNGTRENNUNG
appear in bioactive naturally occurring alkaloids and medici-
nally relevant compounds.[19] To further demonstrate the
synthetic importance of this reaction, we enantioselectively
constructed several different oxindole cores that feature in
alkaloids (Scheme 3). Reductive amination of 4a with ben-
zylamine, followed by condensative cyclization yielded the
lactam in 70% overall yield, which was then decarboxylated
by use of the Krapcho reaction to give a 96% yield of spi-
rooxindole 13, the core structure of communesin.[19c]
Through protection of the aldehyde, Krapcho decarboxyla-
tion, and reduction, 4a could be efficiently converted into
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J. Zhang and R. Liu
Acknowledgements
Financial support from the 973 program (2011CB808600), the National
Natural Science Foundation of China, the Ministry of Educationof China,
and the Ying Tung Education Foundation (121014) is acknowledged. This
research is also supported by the Program for Professor of Special Ap-
pointment (Eastern Scholar) at Shanghai Institutions of Higher Learning.
Keywords: asymmetric synthesis
·
enantioselectivity
·
Michael addition · organocatalysis · oxindoles
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ACHTUNGTNER[NUNG 2,3-
AHCTUNGTRENNUNG
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AHCTUNGTRENNUNG
hexahydrofurano
ACHTUNGTRENNUNG[2,3-b]indole 14, the core structure of phy-
ACHTUNGTRENNUNG
ring-containing spirooxindole 16 in a three step sequence,
the structure of which can be found in welwitindolino-
ne A.[19e]
In summary, we have developed an enantioselective syn-
thesis of 3,3’-disubstituted oxindoles by conjugate addition
of malonates to isatylidene-3-acetaldehyde in high yield and
excellent enantioselectivity. This transformation is easily
scaled up to the gram scale, and its synthetic applications
have been showcased by the enantioselective synthesis of
core skeletons of three indoline-derived alkaloids and the
asymmetric total synthesis of debromoflustramine E in a rel-
atively short route. Further studies, including synthesis of
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Experimental Section
Typical procedure for the organocatalytic addition of malonates to a,b-
unsaturated aldehydes: Malonate 2a (0.5 mmol, 2.0 equiv) was added to
a solution of 3d (18.35 mg, 0.05 mmol, 0.2 equiv), PhCO2H (6.2 mg,
0.05 mmol, 0.2 equiv), and 1a (0.25 mmol, 67.75 mg, 1.0 equiv) in EtOH
(2.5 mL) containing H2O (1.3 equiv) at À208C. The reaction mixture was
stirred for 36 h at À208C and then filtered through a 1–2 cm pad of silica,
washing through with EtOAc and CH2Cl2. The solvents were evaporated
under vacuum. The crude product was purified by silica gel column chro-
matography (CH2Cl2/EtOAc, 15:1) to yield the desired product 4a
(79.9 mg, 81%).
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Michael Addition of Malonates
COMMUNICATION
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Received: March 14, 2013
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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J. Zhang and R. Liu
Organocatalysis
R. Liu, J. Zhang* ............ &&&& — &&&&
Organocatalytic Michael Addition of
Malonates to Isatylidene-3-acetalde-
hydes: Application to the Total
Synthesis of (À)-Debromo-
Flustering oxindoles: An enantioselec-
tive synthesis of 3,3’-disubstituted oxin-
doles by conjugate addition of malo-
nates to isatylidene-3-acetaldehydes in
high yield and enantioselectivity is
developed (see scheme). The synthetic
utility of this reaction is demonstrated
by the synthesis of three oxindole core
structures and the asymmetric total
synthesis of debromoflustramine E.
ACHTUNGTRENNUNGflustramine E
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These are not the final page numbers!