Enantioselective phase-transfer-catalyzed intramolecular Aza-Michael reaction: Effective route to pyrazino-indole compounds

Article abstract of DOI:10.1002/anie.200705685

(Chemical Equation Presented) Producing polycycles: A mild and direct stereocontrolled route to pharmacologically active pyrazino-indol-1-ones has been developed. The optimal phase-transfer conditions provide variously functionalized ring-closed compounds

Full text of DOI:10.1002/anie.200705685

Communications
DOI: 10.1002/anie.200705685
Asymmetric Catalysis
Enantioselective Phase-Transfer-Catalyzed Intramolecular Aza-
Michael Reaction: Effective Route to Pyrazino-Indole Compounds**
Marco Bandini,* Astrid Eichholzer, Michele Tragni, and Achille Umani-Ronchi*
The preparation of enantiomerically pure compounds has
become a stringent requirement for pharmaceutical synthe-
sis.[1] In this context, asymmetric catalysis is probably the most
attractive procedure for the synthesis of active pharmaceut-
ical ingredients (APIs) due to environmental, operational,
and economic benefits.
through regio- and enantioselective C3-allylic nucleophilic
alkylation (up to 97% ee).[7] Unfortunately, all our attempts
to exploit such an approach to perform enantioselective
indolyl-N1 ring-closing reactions were unsuccessful. Herein,
we describe the first highly enantioselective synthesis of
molecular motifs of type 1 through a phase-transfer-cata-
lyzed[8] aza-Michael addition.[9]
3,4-Dihydropyrazino[1,2-a]indol-1(2H)-ones
1
(see
Scheme 1) have attracted much attention due to the broad
The employment of a metal-free approach[10] stems from
our recent findings on the intramolecular base-catalyzed
synthesis of 1, from readily available precursors
3
(Scheme 2).[11] However, the use of Lewis acid catalysis in
Scheme 1. Examples of polycyclic indolyl-based scaffolds. R1 =alkyl,
hydroxyalkyl; R2 =H, Me, Bu; X=H, halogen, alkyl; Y=CH, N.
Scheme 2. Base-catalyzed synthesis of 1. Bn: benzyl; DMSO: dimethyl-
sulfoxide.
scope of their biological activities (that is, their antifungal
properties, noncompetitive antihistamine activity, and specific
inhibition of serotonergic receptors).[2] Moreover, recent
patents reported the effectiveness of the corresponding
1,2,3,4-tetrahydropyrazino[1,2-a]indoles 2 (Scheme 1) as anti-
obesity agents and in the treatment and prevention of non-
insulin-dependent diabetes.[3]
From these studies, the importance of the absolute
configuration of the stereocenters on the pharmacological
activity emerged clearly. Moreover, since the piperazine
compounds 2 are readily obtainable from 1,[3] the develop-
ment of an effective stereoselective synthetic route to
pyrazino-indol-1-ones 1 would be extremely valuable. The
use of chiral pools and the resolution of racemates are the
only synthetic routes to 1 and 2 to date.[3–5]
the present ring-closing reaction failed, probably due to the
poor electrophilic character of the a,b-unsaturated ester and
to low catalyst turnover as a result of starting material/
product inhibition (that is, a metallo-poisoning effect exerted
by the strongly coordinating amide group).
Searching for an enantioselective variant, we firstly turned
our attention to chiral organic bases such as the Cinchona
alkaloids and sparteine, which gave disappointing results in
the cyclizations of 3a (X = H; toluene, reflux, 48 h, 0% ee).
We reasoned that the unsatisfactory stereoinduction could be
ascribable to the formation of flexible and not sufficiently
tight ion pairs between the ammonium salt of the quinuclidine
ring and the nucleophilic indolate intermediate (Figure 1a).
During our ongoing research addressing the functionali-
zation of polycyclic indoles,[6] we recently communicated an
efficient Pd-catalyzed approach to tetrahydro-b-carbolines
[*] Dr. M. Bandini, A. Eichholzer, M. Tragni, Prof. A. Umani-Ronchi
Dipartimento di Chimica “G. Ciamician”
Università di Bologna
Via Selmi 2, 40126 Bologna (Italy)
Fax: (+39)051-209-9456
E-mail: marco.bandini@unibo.it
achille.umanironchi@unibo.it
Homepage: http://www.ciam.unibo.it/organica/MarcoBandini/
index(ita).html
[**] Acknowledgements are made to the MIUR (Rome), Consorzio
C.I.N.M.P.I.S., and University of Bologna. We kindly thank Dr. Paolo
Melchiorre (University of Bologna) for helpful discussions.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Figure 1. Chiral organic bases versus phase-transfer catalysis in the
enantioselective ring closure of 3.
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Chemie
In light of this consideration, we envisioned that the use of
more rigid chiral ammonium salts would guarantee higher
enantioselection (Figure 1b).
The employment of N-benzylcinchonidinium bromide 4a
(10 mol%), in combination with KOH (25% aq; 0.5 equiv)
under a phase-transfer regime, furnished 1a in 84% yield and
active role for the OH group during the enantiodiscrimination
step of the process.[12] Asteady improvement in enantiocon-
trol was obtained by introducing electron-withdrawing sub-
stituents on the benzyl group; these are known to favor
tighter contact ion pairing with consequent strengthening of
the substrate–catalyst interaction.[13] In particular, while a
para-methoxy group (in 4b) causes a marked drop in
enantiocontrol (21% ee; Table 1, entry 2), the introduction
of para-nitro, para-fluoro, and para-CF3 moieties (in 4 f, 4i,
and 4j, respectively) gave 1a with comparable yields (89–
90%) and ee values of 60–61% (Table 1, entries 6, 9, and 10).
Mechanistically, the present intramolecular aza-Michael
addition seems to work quite differently from most of the
described phase-transfer-catalyzed alkylation reactions, in
which a templating effect of molecules of water or cations is
used to rationalize high levels of stereoinduction.[14] In fact, in
our system, comparable enantiomeric excesses were recorded
with several inorganic bases (LiOH, NaOH, and CsOH; solid
and in aqueous solution), and the presence of coordinating
groups at the ortho position of the phenyl ring (in 4e; known
to favor rigid catalyst conformations) led to a marked drop in
induction (Table 1, entry 5). Remarkably, lowering of the
reaction temperature to À20 and À458C caused an increase of
stereoinduction to 72 and 91%, respectively (Table 1,
entries 16 and 17), with no significant variation in the
chemical yield (91–93%).
with a promising 36% ee (toluene, 30 min, 08C; Table 1,
entry 1). Prompted by this result, we undertook a survey of
chiral Cinchona ammonium salts (4b–o) in the cyclization of
the model substrate 3a; the corresponding outcomes are
summarized in Table 1. Interestingly, the free hydroxy group
at the C9 position proved to be crucial to guarantee
reasonable ee values. In fact, the use of the C9-O-allyl catalyst
4c gave 1a in nearly racemic form (Table 1, entry 3). The
inversion of stereoinduction observed with 4c suggests an
With the optimal reaction conditions established, the
substrate scope of the reaction was investigated; the results
are summarized in Table 2. Tolerance toward both electron-
withdrawing and electron-donating groups on the indolyl
scaffold (C5 position) is highlighted by entries 1–4 in Table 2.
Under optimal conditions (4j, 10 mol%), the desired pyra-
zino-indol-1-ones 1b–e were isolated in 85–93% yield and
with enantiomeric excess values of up to 89%. The indolyl
esters bearing electron-donating substituents (Me, OMe) at
Table 1: Screening of chiral catalysts (Cat*: 4a–o) for the enantioselec-
tive ring closure of 3a.[a]
Table 2: Proof of the generality of the method.[a]
Entry
Cat.*
R1/R2/R3
XÀ/Y/Z
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16[d]
17[e]
4a
4b
4c
4d
4e
4 f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4j
H/H/H
OMe/H/H
H/H/H
H/NO2/H
H/H/NO2
NO2/H/H
NO2/H/H
F/F/F
F/H/H
CF3/H/H
CF3/H/H
see structure
NO2/H/H
CF3/H/H
Br/H/H
Cl/H/H
84
82
85
80
81
89
75
90
89
90
75
80
85
90
55
91
93
36
21
Cl/H/allyl
Br/H/H
Br/H/H
Br/H/H
Br/OMe/H
Br/H/H
Br/H/H
Br/H/H
Br/OH/H
À5
52
À6
60
45
33
60
Entry
1
X/Y/Z/R
Yield [%][b]
ee [%][c]
Conf.
1
2
1b
1c
1d
1e
1 f
1g
1h
1i
F/H/Bn/Et
Cl/H/Bn/Et
93
88
85
85
90
55
75
90
61
82
84
89 (98)
89 (96)
75
80
82
90 (92)
53
S
S
S
S
–
–
S
S
S
3[d]
4[e]
5
OMe/H/Bn/Et
Me/H/Bn/Et
H/C6H5/Bn/Et
H/b-naphth[f]/Bn/Et
H/H/PMP[f]/Et
H/H/Bn/Me
H/H/Bn/tBu
61
25
6
7
À8
À30
À25
À7
72
Br/OMe/H
Br/H/H
8[d]
9[d]
1j
see structure
CF3/H/H
CF3/H/H
Br/H/H
Br/H/H
[a] All reactions were carried out in open-air vials with reagent-grade
toluene with KOH (25% aq; 0.5 equiv) at À458C for 16 h, unless
otherwise specified. [b] Yields after isolation by flash chromatography.
[c] Determined by HPLC on a chiral stationary phase. The values given in
brackets are ee values after crystallization (boiling Et2O for 1d and 1e;
cyclohexane for 1i). [d] Reaction time of 48 h. [e] Reaction time of 36 h.
[f] Naphth: naphthalene; PMP: para-methoxyphenyl.
4j
91
[a] All reactions were carried out in open-air vials with reagent-grade
toluene and 10 mol% of catalyst (08C, 16 h, 0.5 equiv of KOH). [b] Yields
after isolation by flash chromatography. [c] Determined by HPLC on a
chiral stationary phase (DAICEL Chiralcel AD). [d] T=À208C. [e] T=
À458C.
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3239

Communications
the C5 position (3d and e; Table 2, entries 3 and 4) underwent
(S)-7 (Scheme 3b).[3] The absolute configuration of the
polycyclic compounds 1b–e and 1h–j was assigned as S by
analogy.
The initial statement concerning the ready interconver-
sion of 1 into 1,2,3,4-tetrahydropyrazino[1,2-a]indoles 2 has
been verified by treating (S)-1a with an excess of LiAlH4
(4 equiv) at 08C. Under these conditions, the corresponding
pyrazino-indole (S)-2a was isolated in 92% yield without any
appreciable racemization (91% ee, Scheme 4).
the cyclization with good stereocontrol but prolonged reac-
tion times were needed to ensure complete conversion (36
and 48 h, respectively). Remarkably, nearly enantiomerically
pure compounds can be readily obtained by recrystallization
from boiling Et2O (3d, 98% ee; 3e, 96% ee). 3-Aryl indole
derivatives 3 f and 3g also smoothly cyclized under the
optimal conditions to afford the corresponding functionalized
pyrazino-indol-1-ones 1 f and 1g in good yields (90 and 55%,
respectively) and with good enantiomeric excess values (75
and 80%, respectively; Table 2, entries 5 and 6). Limitation
on the scope of the reaction lies in the presence of sterically
demanding groups (for example, tBu) at the ester moiety. In
fact, while methyl ester 1i (yield 90%, 90% ee, 92% ee after
crystallization; Table 2, entry 8) confirmed the result
obtained with the model substrate 1a (Table 1, entry 17),
tert-butyl derivative 3j underwent cyclization with only
modest stereodiscrimination (53% ee; Table 2, entry 9).[15]
To the best of our knowledge, only a handful of examples of
Scheme 4. Stereoretentive synthesis of pyrazino-indole 2a from pyra-
zino-indol-1-one 1a.
À
asymmetric organocatalyzed intramolecular C N bond-form-
ing processes, through Michael addition, have been described
In conclusion, we have presented a flexible, mild, and
highly enantioselective approach to 3,4-dihydropyrazino[1,2-
a]indol-1(2H)-ones through phase-transfer catalysis. The
ready availability of the acyclic precursors and the broadness
of scope make the method a general and useful shortcut for
the preparation of a plethora of enantioenriched polycyclic
indolyl-based compounds, even for large-scale productions.
to date.[16]
The absolute configuration of 1a was determined to be S
by chemical correlation to the pyrazino-indol-1-one (R)-5
(Scheme 3). In particular, from enantiomerically enriched 1a
(88% ee), the saponification of the ester moiety followed by a
radical decarboxylation reaction (with Bartonꢀs reagent[17]) of
the corresponding acid chloride led to compound (S)-5 with
88% ee in three steps (Scheme 3a). The chemical correlation
(specific optical rotation and chiral HPLC retention times; Experimental Section
Representative procedure for the synthesis of 1a: Asample vial was
see the Supporting Information) was carried out by exploiting
the known multistep approach for the synthesis of pyrazino-
indol-1-ones from enantiomerically pure cyclic sulfamidate
charged with reagent-grade toluene (6 mL), the indolyl ester 3a
(20 mg, 50 mmol), and the phase-transfer catalyst 4j (3 mg, 5 mmol).
An aqueous solution of KOH (25%, 6 mL, 0.5 equiv) was added
through a syringe, and the mixture was immediately cooled to À458C.
The reaction was stirred at the same temperature for 16 h, then the
solvent was evaporated under reduced pressure. The crude product
was directly purified through a pad of silica (cyclohexane/EtOAc
80:20) to give (S)-1a as a white solid in 93% yield and 91% ee (see
the Supporting Information).
Received: December 12, 2007
Revised: January 25, 2008
Published online: March 17, 2008
Keywords: asymmetric catalysis · cyclization · indoles ·
.
Michael addition · phase-transfer catalysis
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