Organocatalytic enantioselective multicomponent synthesis of pyrrolopiperazines

Article abstract of DOI:10.1002/adsc.201300932

The first organocatalytic multicomponent synthesis of enantioenriched pyrrolopiperazines is reported. These biologically relevant fused tricyclic products were obtained under catalytic iminium activation through a reaction sequence involving an enantioselective Michael addition followed by an iminium ion trapping via Pictet-Spengler cyclization (MAPS sequence). Substantial possibilities for variation on the three reaction partners [β-keto ester, enal and N-(2-aminoethyl)pyrrole] along with excellent enantioselectivities are the highlights of the present transformation.

Full text of DOI:10.1002/adsc.201300932

UPDATES
DOI: 10.1002/adsc.201300932
Organocatalytic Enantioselective Multicomponent Synthesis of
Pyrrolopiperazines
Haiying Du,a Jean Rodriguez,a Xavier Bugaut,a,* and Thierry Constantieuxa,*
a
Aix Marseille Universitꢀ, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397 Marseille, France
Fax : (+33)-491-289-187; phone: (+33)-491-288-391; e-mail: xavier.bugaut@univ-amu.fr or
thierry.constantieux@univ-amu.fr
Received: October 20, 2013; Revised: December 4, 2013; Published online: March 3, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300932.
Abstract: The first organocatalytic multicomponent
synthesis of enantioenriched pyrrolopiperazines is
reported. These biologically relevant fused tricyclic
products were obtained under catalytic iminium ac-
tivation through a reaction sequence involving an
enantioselective Michael addition followed by an
iminium ion trapping via Pictet–Spengler cycliza-
tion (MAPS sequence). Substantial possibilities for
variation on the three reaction partners [b-keto
ester, enal and N-(2-aminoethyl)pyrrole] along with
excellent enantioselectivities are the highlights of
the present transformation.
ene (Scheme 1).[4,5] The previously unknown tricyclic
pyrrolopiperazines 4 were obtained in good yields.
Even though the bioactivity of this specific class of
compounds has not been evaluated yet, the diverse
biological activities of other pyrrolopiperazines[6] pro-
motes interest for the development of simple synthet-
ic methodologies for the enantioselective preparation
of these heterocycles.[7]
In 2009, Franzꢀn and co-workers identified iminium
activation using chiral secondary amine catalyst (S)-
I
[8] to control the enantioselection in bimolecular step-
wise MAPS sequences.[9] 1,3-Dicarbonyl compounds
functionalized with a pendant electron-rich (hetero)-
arene were coupled with cinnamaldehyde derivatives
to afford quinolizidines, and an acid additive was re-
quired for the final cyclization step [Scheme 2, Eq.
(1)]. Soon afterwards, Wu, Zhao and co-workers re-
ported the one-pot consecutive enantioselective
MAPS sequence with tryptamines as the third cou-
pling partner in the presence of benzoic acid, leading
Keywords: enantioselectivity; Michael addition;
multicomponent reactions; organocatalysis; pyrro-
lopiperazines
The generation of molecular complexity and diversity to the formation of the indoloquinolizidine scaffold
is a central focus in the development of new method- [Scheme 2, Eq. (2)].[10] Later on, conceptually similar
ologies in organic synthesis. To that purpose, multiple bimolecular or sequential transformations have been
bond-forming transformations are one of the most ef- published.[11,12] Even though diversified (hetero)arenes
ficient tools organic chemists have at their disposal.[1] can be used in all these MAPS sequences, this is not
Among them, multicomponent reactions are especial- the case for pyrroles:[9b] their acid sensitivity or their
ly appealing for several reasons:[2] (i) they usually do potential direct addition to the activated enal are pos-
not require the preparation of highly elaborated start-
ing materials; (ii) variations can be made on the dif-
ferent reactions partners; (iii) their operating condi-
tions are often simple. Over the past decade, our
group has been working on the development of new
multicomponent reactions that are initiated by the
Michael addition of a 1,3-dicarbonyl compound.[3] In
particular, we reported the first racemic multicompo-
nent reaction consisting of a Michael addition fol-
lowed by an iminium ion trapping via Pictet–Spengler
cyclization (MAPS sequence), by combining a b-keto
ester 1a, acrolein 2 and N-(2-aminoethyl)pyrrole 3a in
Scheme 1. Racemic multicomponent synthesis of pyrrolopi-
perazines via a Michael addition/Pictet–Spengler (MAPS)
the presence of 4ꢁ molecular sieves in refluxing tolu- sequence.
Adv. Synth. Catal. 2014, 356, 851 – 856
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Haiying Du et al.
(3)]. The key features of the present transformation
are: (i) it represents the first example of an enantiose-
lective multicomponent MAPS sequence, with very
simple operating conditions; (ii) the three reaction
partners are commercially available or easily pre-
pared;[19] (iii) the products are formed in interesting
chemical yields for a multicomponent reaction that
uses fragile pyrrole substrates and creates four new
bonds and two cycles; (iv) excellent enantioselectivi-
ties (>90% ee) are uniformly observed on a wide
range of diversified substrates; (v) in most cases, the
two diastereomers of the product can be separated by
traditional flash chromatography, allowing for the fast
generation of molecular diversity.
We started our investigations by mixing b-keto
ester 1a, cinnamaldehyde 5a and N-(2-aminoethyl)-
pyrrole 3a in toluene in the presence of catalyst I at
08C for two days (Table 1, entry 1). The expected
fused tricyclic pyrrolopiperazine 6a was obtained in
an encouraging yield (63%), as a ~1:1 mixture of two
diastereomers. This result highlights the possibility for
3a to participate in the final Pictet–Spengler cycliza-
tion without the need of using an acid additive, cor-
roborating our initial hypothesis. Pleasingly, enantio-
meric excesses higher than 90% were observed for
both diastereomers. The absolute configurations of
the products were determined by analogy with related
organocatalytic Michael additions,[20] while the rela-
tive configurations of the two diastereomers were as-
signed by NMR.[21] Other secondary amine catalysts
that were screened proved disappointing (entries 2–
5).
As expected, the use of benzoic acid as a co-cata-
lyst (20 mol%) resulted in a lower yield of product 6a
(Entry 6). Moreover, an attempt to run a sequential
reaction in the presence of this acidic additive was
carried out (entry 7). The sensitive pyrrole reactant 3a
Scheme 2. Different strategies for enantioselective MAPS
sequences.
sible explanations.[13] To fill this gap, we propose to was added after two days and the reaction mixture
use highly nucleophilic[14] N-(2-aminoethyl)pyrroles 3 kept at 08C for an additional day. Despite the good
to design a complementary enantioselective multi- yield, a significant erosion of the enantiomeric excess
component MAPS sequence. This strategy could of both diastereomers was observed (down to 86%
avoid the requirement of an acid additive to complete and 82%, respectively). This phenomenon could be
the final Pictet–Spengler cyclization,[15] thereby avoid- ascribed to a reversibility-induced racemization of the
ing the possible acid-mediated degradation of the intermediate Michael adduct, as already observed in
electron-rich pyrrole ring. Moreover, while the related related transformations by the groups of Jørgensen
reactions create a tetrahydropyridine ring, the fact and Rovis.[20,22] Running the reaction in a multicompo-
that the aminoalkyl chain is linked to the nitrogen nent fashion then clearly appears as an efficient strat-
atom results in the formation of a piperazine scaffold. egy to prevent the loss of optical purity of racemiza-
Last but not least, this sequence would represent one tion-sensitive reactive intermediates.
of the first examples of an enantioselective multicom-
Variations of the reaction temperature around 08C
ponent reaction[16] involving the Michael addition of did not lead to an improvement of the results. Even if
a 1,3-dicarbonyl compound as the enantiodiscriminat- increasing the temperature allowed us to obtain
ing step.[17,18]
higher yields, this positive effect was at the cost of
We now wish to report how iminium activation can a slightly reduced enantioselecticity (entry 8). Quite
efficiently catalyze the proposed enantioselective unexpectedly, decreasing the reaction temperature to
three-component reaction between b-keto esters, À108C severely impeded the enantioselectivity
enals and N-(2-aminoethyl)pyrroles 3 [Scheme 2, Eq. (entry 9).
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Organocatalytic Enantioselective Multicomponent Synthesis
Table 1. Optimization of the reaction conditions.[a]
With these optimized conditions in hands, the scope
of the reaction was studied by making modifications
of all three starting materials. At first, the influence
of the bulkiness of the ester group was investigated
(Table 2): ethyl, methyl, isopropyl and tert-butyl sub-
stituents all provided the expected products 6a–d with
good yields and enantiomeric excesses higher than
90% (entries 1-4): it was a little bit lower for the
methyl ester and culminated to 98% for its isopropyl
counterpart. Moreover, the reaction could also be run
on a 2-mmol scale while preserving the yield and the
enantioselectivity (entry 5). The ketone substituent
could also be varied. The replacement of the methyl
group by an ethyl chain tended to increase the yield
of product 6e (entry 6). Aromatic ketones were tricki-
er substrates: the reaction temperature had to be low-
ered to À108C to ensure a good enantioselectivity,
but at the cost of a lower yield, and the two diastereo-
mers of product 6f, obtained as a ~1.4:1 ratio, could
not be separated (entry 7).
Entry
Catalyst
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
I
toluene
toluene
toluene
CHCl3
CHCl3
toluene
toluene
toluene
toluene
CHCl3
C6F6
63
20
7
5
10
46
69
66
93, 90
31, 29
6, 5
9, 4
6, 2
97, 90
86, 82
89, 85
65, 55
82, 75
90, 89
96, 94
II
III
IV
V
I
I
I
I
I
I
I
5
Different a,b-unsaturated aldehydes were then ex-
posed to the standard reaction conditions in the pres-
ence of tert-butyl acetoacetate 1d and N-(2-amino-
6[d]
7[d,e]
8[f]
9[g]
10
11
12
AHCTUNGTREGeNNNU thyl)pyrrole 3a (Table 3). All the aromatic-substitut-
45
77
70
ed aldehydes that were used provided the expected
products 6g–l with reasonable yields and high enan-
tioselectivities, no matter whether they were substitut-
CF3C6H5
68 (35, 33)[h]
[a]
b-Keto ester 1a (0.2 mmol, 1 equiv.), cinnamaldehyde 5a
(0.3 mmol, 1.5 equiv.), N-(2-aminoethyl)pyrrole 3a
(0.2 mmol, 1 equiv.) and catalyst I–V (20 mmol, 10 mol%)
were mixed in the selected solvent (2.5 mL) at 08C for 2
d.
Yield of expected pyrrolopiperazine 6a. The two diaste-
reomers were not separated (~1:1 dr).
Enantiomeric excesses of the two diastereomers were de-
termined by HPLC analysis on a chiral stationary phase.
Benzoic acid (40 mmol, 20 mol%) was added as a co-cata-
lyst.
Sequential reaction: 3a was added only after two days of
reaction, and the reaction mixture stirred on for one
more day.
Table 2. Scope of b-keto esters.[a]
[b]
[c]
[d]
[e]
Entry
Product
R1
R2
Yield [%][b]
ee [%]
[f]
Reaction was run at room temperature.
Reaction was run at À108C.
[g]
[h]
1
2
3
6a
6b
6c
6d
6d
6e
6f
Me
Me
Me
Me
Me
Et
Et
68 (35, 33)
53 (33, 20)
54 (23, 31)
70 (33, 37)
56 (27, 29)
70 (38, 32)
40[e]
96, 94
90, 92
98, 96
92, 95
92, 94
95, 91
94, 93
Me
i-Pr
t-Bu
t-Bu
Me
Et
The two diastereomers were separated.
4
5[c]
6
Compared to toluene (entry 1), CHCl3 as the sol-
vent improved the yield but diminished the enantio-
meric excess (entry 10). Fluorinated aromatic solvents
such as hexafluorobenzene (entry 11),[23] and trifluoro-
toluene (entry 12) were also very efficient, the latter
one affording the product with 68% yield and 96%
and 94% ee. The diastereomeric ratio remained close
to 1:1.[24] However, the two diastereomers could be
separated by flash chromatography, giving the oppor-
tunity to quickly generate a library of diversified
products, an interesting feature in the context of the
preparation of potentially bioactive compounds.
7[d]
Ph
[a]
b-Keto ester 1a–f (0.2 mmol, 1 equiv.), cinnamaldehyde
5a (0.3 mmol, 1.5 equiv.), N-(2-aminoethyl)pyrrole 3a
(0.2 mmol, 1 equiv.) and catalyst I (20 mmol, 10 mol%)
were mixed in trifluorotoluene (2.5 mL) at 08C for 2 d.
Yield of expected pyrrolopiperazines 6a–f, as two separa-
ble diastereomers.
[b]
[c]
[d]
[e]
Reaction was run on a 2 mmol scale.
Reaction was run at À108C.
The two diastereomers could not be separated (~1.4:1
dr).
Adv. Synth. Catal. 2014, 356, 851 – 856
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UPDATES
Haiying Du et al.
Table 3. Scope of a,b-unsaturated aldehydes.[a]
Table 4. Scope of N-(2-aminoethyl)pyrroles.[a]
Entry
Product
R3
Yield [%]
ee [%]
Entry Product R4
R5 R6
Yield [%]
ee [%]
1
2
3
4
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
4-MeO-C6H4
4-Cl-C6H4
4-NO2-C6H4
2-MeO-C6H4
2-NO2-C6H4
2,4-diCl-C6H3
2-furyl
3-thienyl
Me
n-Pr
63 (40, 23)
50 (34, 16)
53 (23, 30)
51 (21, 30)
53 (29, 24)
52 (20, 32)
31 (14, 17)
44 (27, 17)
33[c]
94, 92
99, 91
95, 94
89, 90
97, 98
94, 96
74, 92
97, 94
88
1
2
3
4
5
6
6q
6r
6s
6t
6u
6w
Me
vinyl
Ph
H
Me
H
H
H
Ph
H
H
H
H
H
54 (17, 37)
61 (25, 36)
69 (26, 43)
34 (17, 17)
97, 93
92, 94
94, 93
95, 97
n.d.
5
6
7[b]
8
Me traces
-(CH)4-
Me no product n.d.
9
10
[a]
Reaction conditions are identical to those in Table 2.
39[c]
92
[a]
Reaction conditions are identical to those in Table 2.
Reaction was run at À208C.
[b]
[c]
Only the cis diastereomer was isolated.
ed with electron-donating (entries 1 and 4) or elec-
tron-withdrawing groups (entries 2, 3, 5 and 6). Nota-
bly, the enantiomeric excess reached 99% in the case
of 4-chlorocinnamaldehyde (entry 2). A small de-
crease of enantioselectivity could be noted only in the
case of 2-methoxycinnamaldehyde (entry 4). With
highly reactive 3-(2-furyl)acrolein, the temperature
had to be decreased to À208C to ensure good enan-
tioselectivity but this modification of the reaction con-
ditions also resulted in a lower yield of product 6m
Scheme 3. Hydrogenation of the enamino ester moiety.
(entry 7). In contrast, the pyrrolopiperazine 6n deriv- other by-products (entry 5).[7c] Besides this, the corre-
ing from 3-(3-thienyl)acrolein was formed with high sponding N-(2-aminoethylindole) 3w did not provide
selectivity under the standard reaction conditions any product in these acid-free conditions, highlighting
(entry 8).
b-Alkyl aldehydes also participated in the transfor- Spengler cyclization of less nucleophilic aromatics.
mation (entries 9 and 10). However, the reaction was To further extend the synthetic usefulness of this
the requirement of an acid to promote the Pictet–
more sluggish, so that only the cis-diastereomers of multicomponent reaction, the double bond of the en-
products 6o, p could be isolated in pure form, albeit amino ester moiety was reduced with hydrogen gas in
with reduced enantioselectivity.
the presence of Adamsꢃ catalyst (Scheme 3).[25] Pleas-
At last, modifications of the third reaction partner ingly, product 7 was obtained in excellent yield and
were envisaged (Table 4). 2-Methyl, 2-vinyl or 2- the two newly created stereogenic centers were
phenyl-substituted pyrrole derivatives afforded the formed with complete diastereoselectivity.[21]
expected products 6q–u with high efficiency (en-
In summary, we have developed a new enantiose-
tries 1–3). A phenyl substitution on position 3 was lective three-component reaction between b-keto
also accommodated and delivered product 6t in good esters, enals and N-(2-aminoethyl)pyrroles that results
enantioselectivity but with reduced yield (entry 4). A in the formation of original and biologically relevant
limitation of the transformation was attained with the fused tricyclic piperazines. Further elaboration of this
use of very electron-rich pyrrole derivatives:[14] only heterocyclic scaffold and the study of its biological ac-
traces of pyrrolopiperazine 6u were observed, along tivity stand on our work plan. We will also maintain
with the product of direct Pictet–Spengler annulation our efforts towards the development of new organo-
of N-(2-aminoethylpyrrole) 3u with the aldehyde, and catalytic multicomponent reactions.
854
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Organocatalytic Enantioselective Multicomponent Synthesis
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Experimental Section
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General Procedure
A reaction tube was charged with (S)-(À)-a,a-diphenyl-2-
pyrrolidinemethanol trimethylsilyl ether
I
(6.6 mg,
0.020 mmol, 0.1 equiv.), dry a,a,a-trifluorotoluene (2.5 mL),
flushed with argon and placed at 08C. b-Keto ester 1a–f
(0.200 mmol, 1 equiv.) was then added followed by freshly
distilled a,b-unsaturated aldehyde 5a, 5g–p (0.300 mmol,
1.5 equiv.)
and
N-(2-aminoethyl)pyrrole
3a,
3q–t
(0.200 mmol, 1 equiv.). After 2 days, the solution was direct-
ly purified by flash column chromatography on silica gel to
provide the pyrrolopiperazines 6a–t as two separable diaste-
reomers.
Acknowledgements
We warmly thank Dr. N. Vanthuyne and M. Jean for HPLC
analyses, and the whole team of the Spectropole (www.spec-
tropole.fr). Financial support from Aix Marseille Universitꢀ,
Centrale Marseille, the CNRS, the COST action CM0905
ORCA, and the China Scholarship Council (scholarship for
H.D.) is acknowledged.
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[21] See the Supporting Information for further details.
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[24] Diastereomeric ratios before purification could not be
determined precisely because of the lack of sufficiently
1
resolved signals in the H NMR spectra. Moreover, if
the products were not directly purified by flash chro-
matography at the end of the reaction, an erosion of
the enantiomeric excess was observed (probably during
the evaporation of the solvent in the presence of the
catalyst). Besides this, crossover studies (detailed in the
Supporting Information) showed that the final cycliza-
tion step is not reversible, so that this mixture of diaste-
reomers is not the result of an equilibration.
[18] We recently reported the use of b-keto amides in
a three-component reaction involving a Michael addi-
tion to acrolein as the enantiodiscriminating step:
[25] Y. Zhang, A. I. Gerasyuto, Q. A. Long, R. P. Hsung,
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Adv. Synth. Catal. 2014, 356, 851 – 856