Catalytic Asymmetric Reactions of 4-Substituted Indoles with Nitroethene: A Direct Entry to Ergot Alkaloid Structures

Article abstract of DOI:10.1002/chem.201502655

A domino Friedel-Crafts/nitro-Michael reaction between 4-substituted indoles and nitroethene is presented. The reaction is catalyzed by BINOL-derived phosphoric acid catalysts, and delivers the corresponding 3,4-ring-fused indoles with very good results in terms of yields and diastereo- and enantioselectivities. The tricyclic benzo[cd]indole products bear a nitro group at the right position to serve as precursors of ergot alkaloids, as demonstrated by the formal synthesis of 6,7-secoagroclavine from one of the adducts. DFT calculations suggest that the outcome of the reaction stems from the preferential evolution of a key nitronic acid intermediate through a nucleophilic addition pathway, rather than to the expected "quenching" through protonation.

Full text of DOI:10.1002/chem.201502655

DOI: 10.1002/chem.201502655
Communication
&
Asymmetric Synthesis
Catalytic Asymmetric Reactions of 4-Substituted Indoles with
Nitroethene: A Direct Entry to Ergot Alkaloid Structures
Simone Romanini,[a] Emilio Galletti,[a] Lorenzo Caruana,[a] Andrea Mazzanti,[a] Fahmi Himo,[b]
Stefano Santoro,*[c] Mariafrancesca Fochi,*[a] and Luca Bernardi*[a]
members of this class of natural compounds have been report-
Abstract: A domino Friedel–Crafts/nitro-Michael reaction
ed, with the archetype lysergic acid having been the most pur-
between 4-substituted indoles and nitroethene is present-
sued.[3] Concurrently, the construction of the synthetically chal-
ed. The reaction is catalyzed by BINOL-derived phosphoric
lenging 1,3,4,5-tetrahydrobenzo[cd]indole scaffold has recently
acid catalysts, and delivers the corresponding 3,4-ring-
received considerable attention, even in its unadorned and rac-
fused indoles with very good results in terms of yields and
emic/achiral forms.[4] In this context, we have reported an
diastereo- and enantioselectivities. The tricyclic benzo[c-
enantioselective approach to this scaffold, based on the orga-
d]indole products bear a nitro group at the right position
nocatalytic domino reaction of indoles 1 bearing a Michael ac-
ceptor at the 4-position with a,b-unsaturated aldehydes.[5]
to serve as precursors of ergot alkaloids, as demonstrated
by the formal synthesis of 6,7-secoagroclavine from one
The domino reaction of these substrates 1 with nitroe-
thene[6] 2 leads to benzo[cd]indoles 3 having the nitro group
of the adducts. DFT calculations suggest that the outcome
of the reaction stems from the preferential evolution of
at a strategic position to serve as precursors of ergot alkaloids
a key nitronic acid intermediate through a nucleophilic ad-
(Figure 1b). This reaction has been attempted with a view to
dition pathway, rather than to the expected “quenching”
ergot synthesis. However, results were disappointing and the
through protonation.
reaction was thus discarded in favor of less direct routes for
compounds related to 3.[4d,7,8] We hypothesized that recent ad-
vances in the activation of nitro compounds by weak H-bond
donor catalysts[9] could offer a solution for this transformation,
Ergot alkaloids have been the subject of longstanding inter-
est.[1] Besides being the causative agents of the serious disease
giving also an unprecedented stereocontrolled access to com-
ergotism and used as hallucinogenic drugs, ergot alkaloids and
derivatives have seen their powerful biological activities sub-
dued for medical purposes. Pharmaceutical usefulness arises
from subtle modifications of their naturally occurring struc-
tures, which feature a distinctive tricyclic 4-amino-1,3,4,5-tetra-
hydrobenzo[cd]indole framework with a modified methallyl
residue at the 5-position, often fused within an additional ring
(Figure 1a). Biosynthetically derived from tryptophan through
intriguing enzymatic pathways,[2] total syntheses of several
pounds 3. However, initial experiments (Figure 1c) showed
that thiourea catalysts that were useful in simpler Friedel–
Crafts (FC) reactions[10] were not able to promote any reaction
between substrates 1a–c and nitroethene 2, possibly due to
the known[5a] poor nucleophilicity of indoles 1. A more acidic
BINOL-derived phosphoric acid[11] catalyst, such as PA1, proved
instead to be useful. Substrate 1a furnished with promising
enantioselectivity and as a single trans-diastereoisomer the de-
sired product 3a with moderate (70%) conversion. This result
was somewhat unexpected. The reaction should proceed
through a nitronate/nitronic acid, formed upon the FC addi-
tion. In principle, the PA catalyst should be able to easily
“quench” this species through protonation, due to its acidity.[12]
Indeed, the presence of a competition between nitro-Michael
and “quenching” pathways was revealed by the exclusive for-
mation of the side product 3’ not only in the reaction with
indole 1b featuring a weak ester Michael acceptor, but also
with 1c bearing an N-acyl pyrrole, an efficient moiety for nitro-
Michael reactions (Figure 1c).[13] It is worth stressing that only
few examples of organocatalytic domino reactions[14] have
dealt with this type of sequential process (H-bond-promoted
addition of a neutral nucleophile triggering a subsequent
transformation),[15] none of which has involved a phosphoric
acid as catalyst.
[a] S. Romanini, E. Galletti, Dr. L. Caruana, Prof. A. Mazzanti, Prof. M. Fochi,
Prof. L. Bernardi
Department of Industrial Chemistry “Toso Montanari”
University of Bologna, V. Risorgimento 4, 40136 Bologna (Italy)
E-mail: mariafrancesca.fochi@unibo.it
luca.bernardi2@unibo.it
[b] Prof. F. Himo
Department of Organic Chemistry, Arrhenius Laboratory
Stockholm University, 10691 Stockholm (Sweden)
[c] Dr. S. Santoro
Department of Chemistry, Biology and Biotechnology
University of Perugia, V. Elce di Sotto 8, 06123 Perugia (Italy)
E-mail: stefano.santoro@unipg.it
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502655.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of Creative Commons Attri-
bution NonCommercial-NoDerivs. License, which permits use and distribu-
tion in any medium, provided the original work is properly cited, the use is
non-commercial and no modifications or adaptations are made.
Prior to embarking on the study and optimization of the re-
action, we decided to resort to a computational approach to
shed some light on the reaction pathway of this unusual phos-
Chem. Eur. J. 2015, 21, 17578 – 17582
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Communication
to nitroalkenes[16] focused on the CÀC bond-forming
step, neglecting subsequent H-transfer events (i.e.,
rearomatization and nitronate protonation) that are
crucial in this cascade process, dictating its evolution.
Here, several pathways following the first CÀC bond
formation can, in principle, be envisaged. The FC re-
action might evolve through a H-relay process releas-
ing the catalyst and a chiral indolenine. Alternatively,
catalyst-coordinated nitronic acid intermediates
could form upon indole rearomatization or NÀH ab-
straction. Besides, indole rearomatization might occur
prior to or after the Michael addition step. These hy-
potheses were evaluated by DFT calculations using
the B3LYP-D functional (see the Supporting Informa-
tion for details), studying the full catalytic cycle for
the reaction between nitroethene 2 and the methyl
ketone derivative 1d, chosen as a model of sub-
strates bearing a ketone Michael acceptor. We used
the phosphoric acid derived from [1,1’-biphenyl]-2,2’-
diol as a model of BINOL-derived chiral phosphoric
acids (Figure 2).
First, two possibilities were found for the initial nu-
cleophilic attack of the indole on electrophile 2. In
the first case (TS1) the catalyst coordinates to both
the nitro group and the indole NÀH, whereas in the
second (TS1’), it coordinates to the nitro group and
the C3ÀH of the indole. In both cases, protonation of
the nitro group occurs concertedly with the expected
CÀC bond formation.[17] The reaction occurring
through TS1 is favored by 6.4 kcalmolÀ1 over TS1’, in
line with the previously determined pathway fol-
lowed in related FC processes.[16a] While NÀH abstrac-
Figure 1. Ergot alkaloid structures and domino reaction of indoles 1 with nitroethene 2.
a) Some naturally occurring and semisynthetic ergot alkaloid derivatives (the 1,3,4,5-tet-
rahydrobenzo[cd]indole framework is highlighted); b) Friedel–Crafts (FC)-triggered nitro-
Michael reaction en route to ergot alkaloids; c) preliminary results: thioureas do not pro-
mote the reaction. Phosphoric acids can catalyze the reaction, by two competing path-
ways (nitro-Michael vs. intermediate “quench”).
phoric acid-catalyzed transformation. Previous computational
studies of the phosphoric acid-catalyzed FC addition of indoles
tion was not productive, a TS for the indole rearomatization
through C3-deprotonation (TS2) was located, associated with
Figure 2. Free energy profile for the formation of products 3d and 3’d from the reaction between (E)-4-(1H-indol-4-yl)but-3-en-2-one (1d) and nitroethene 2.
See the Supporting Information for optimized ball-and-stick structures.
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Communication
an energy barrier of 18.7 kcalmolÀ1 relative to the reactants.
This step does not occur through a proton-relay process re-
leasing the catalyst, but leads instead to intermediate INT2. Al-
ternatively, we have found that a direct cyclization could occur
before rearomatization through TS2’. However, the energy bar-
rier for this possibility is higher than that for the rearomatiza-
tion (23.9 vs. 18.7 kcalmolÀ1), which makes this option less
likely.[18] After the rearomatization, a nitro-Michael addition can
occur with the catalyst coordinating to both the nitro group
and the carbonyl moiety (TS3). In this step, associated with
a low energy barrier (10.3 kcalmolÀ1), the deprotonation of the
nitro group and the protonation of the carbonyl occur concert-
edly with the trans-selective CÀC bond formation.[19] After cycli-
zation through TS3, a keto–enol tautomerization is required to
generate final product 3d. We found that the catalyst can also
promote this process through TS4, with a low barrier.
Scheme 1. Representative screening results.
Table 1. Scope of the catalytic enantioselective domino reaction.[a]
As discussed above, the formation of cyclized product 3 is in
competition with the formation of side-product 3’. This can be
formed if INT2 evolves through a nitronic acid–nitro tautomeri-
zation, instead of the cyclization. A transition state (TS3’) with
an energy barrier of 20.7 kcalmolÀ1 relative to INT2, and in-
volving the catalyst, was identified for this tautomerization.
The energy required for this step is likely overestimated by our
calculations,[20] with TS3’ being the best approximation we
have found. Nevertheless, given the exclusive formation of cy-
clized product 3d, it can be concluded that the energy re-
quired for this tautomerization should be higher than about
13 kcalmolÀ1 relative to INT2.[20]
To summarize, the reaction occurs through a nucleophilic
attack of the indole 1 on nitroethene 2, followed by a rearoma-
tization occurring before the cyclization and ensuing keto–
enol tautomerization. The catalyst is involved in all steps, in-
cluding the stereodetermining cyclization event, accounting
for the enantioenrichment of product 3a when an enantiopure
catalyst was used (Figure 1c). A rather high energy barrier as-
sociated with the nitronic acid–nitro tautomerization step (ni-
tronate “quench”) makes the cyclization to the desired prod-
ucts 3 possible and prevailing even with an acidic catalyst, pro-
vided that a highly reactive Michael acceptor is employed (i.e.,
TS3 energy is sufficiently low).
Entry
1
R1
R2
R3
Yield[b] [%]
ee[c] [%]
1
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Ph
OMe
pyrrol-1-yl
Me
4-MeOC6H4
4-BrC6H4
4-MeC6H4
2-naphthyl
tBu
CH(OMe)2
Ph
Ph
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
allyl
3a: 95
3’b: 62
3’c: 94
3d: 96
3e: 91
3 f: 95
3g: 98
3h: 98
3i: 90
3j: 82
3k: 90
3l: 75
3m: 70
97
–
–
2[d]
3[d]
4
54
97
97
98
>99
93
96
94
95
93
5
6
7
8
9
10[e]
11
12[f]
13[g]
1j
1k
1l
1m
Ph
[a] Conditions: indole 1 (0.10 mmol), PA2 (0.005 mmol, 5 mol%), nitroe-
thene 2 (1.5m toluene solution, 0.15 mmol), dry MgSO4 (30 mg), CH2Cl2
(300 mL), 08C, 60 h, then filtering through a plug of silica gel, solvent
1
evaporation, and analysis by H NMR spectroscopy; d.r. of products 3 was
found to be >95:5 in all cases. [b] After chromatography on silica gel.
[c] Determined by chiral stationary phase HPLC. [d] In the presence of 4 Š
MS instead of MgSO4, RT, 24 h. [e] RT, 24 h. [f] 0.225 mmol 2. [g] PA2
(0.0075 mmol, 7.5 mol%), RT.
To optimize the catalytic asymmetric version of the reaction,
we screened various chiral phosphoric acid catalysts[11] and re-
action conditions, using 1a as substrate in the reaction with ni-
troethene 2 (see the Supporting Information and Scheme 1).
This screening initially identified catalyst PA2 [(R)-TRIP,
10 mol%], a solvent that is non-coordinating but able to solu-
bilize indole 1a (CH2Cl2), and ambient temperature as suitable
conditions to afford 3a with very good results. We then tested
dehydrating agents as additives, in order to increase the cata-
lyst activity. Activated molecular sieves (3, 4, or 5 Š) gave
scarcely reproducible results, and surprisingly shifted occasion-
ally the reaction pathway towards the open-chain adduct
3’a.[21] The obtainment of 3’a allowed us to perform a control
experiment (see the Supporting Information) confirming the
expected[12] and computed (Figure 2) incapability of the cata-
lyst to resume 3’a to 3a. Instead, we found that MgSO4 as
drying agent had a beneficial effect, allowing a reduced cata-
lyst loading and a lower reaction temperature, leading to in-
creased enantioselectivity.
We then applied these conditions to substrates 1a–m bear-
ing different Michael acceptor groups and indole cores. The re-
sults (Table 1) show that, besides the simple phenyl derivative
1a (entry 1), other electronically/sterically different aryl accept-
ors in 1e–h provided the corresponding products 3e–h with
excellent results (entries 5–8). The ester and N-acyl pyrrole de-
rivatives 1b and 1c gave exclusively the open-chain adducts
3’b and c, even under the optimized conditions. Molecular
sieves provided better yields than MgSO4 in these simple FC
reactions (Table 1, entries 2 and 3).[21] The methyl ketone sub-
strate 1d unfortunately gave a reduced enantioselectivity in
the product 3d (Table 1, entry 4). However, the reaction scope
is not restricted to Michael acceptors bearing aryl groups. Sub-
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strates 1i and 1j, bearing a tert-butyl and a dimethoxymethyl
substituent at the ketone, respectively, afforded the products
3i and j with excellent results (Table 1, entries 9 and 10), sug-
gesting that it is the bulkiness of the acceptor that is essential
to achieving excellent enantiocontrol in this reaction. As ex-
pected, the 2-methylindole derivative 1k performed very well
in the reaction (Table 1, entry 11). In contrast with simpler FC
reactions, wherein catalyst coordination to the indole NÀH is
generally required for enantioselectivity,[16] the computed path-
way of this transformation predicts this interaction to be
absent in the stereodetermining step (Figure 2, TS3), while
being useful for reactivity, as it is related to the RDS (TS1 vs.
TS1’). Indeed, the products 3l and m, derived from the N-alkyl
substrates 1l and m, were obtained with excellent enantiose-
lectivities, although slightly modified conditions were required
to achieve good yields (Table 1, entries 12 and 13).
Scheme 2. Reaction with substrate 1n and elaboration of product 3n.
trans products 3 with very good results. As revealed by DFT
calculations, the reaction is a unique example of evolution of
a nitronate/nitronic acid intermediate towards a nucleophilic
pathway, in favor of the ordinary “quench” of this intermediate
through protonation. The benzo[cd]indole products 3 feature
a nitro group at a strategic position to serve as ergot alkaloid
precursors. Since diastereoisomer equilibration in MeOH favors
the cis isomers (4), all four stereoisomers of the tricyclic system
can be potentially accessed with this methodology.
Treatment of 3a with NaOH in MeOH caused equilibration
favoring the cis stereoisomer 4a [Eq. (1)]. DFT calculations indi-
cated that this cis isomer (4a) is more polar than the trans
(3a), and thus accounted for 4a being favored in a polar
medium such as MeOH. Equilibration occurred through a selec-
tive epimerization at the a-nitro stereogenic center and not
through a retro-nitro-Michael pathway that would have led to
racemization. We determined the relative configuration of
compounds 3a and 4a as trans and cis, respectively, by a thor-
ough computational (DFT) and NMR analysis (see the Support-
ing Information). Their absolute configuration was inferred as
shown by comparing the calculated (TD-DFT) with the experi-
mental Electronic Circular Dichroism (ECD) spectra.[22]
Acknowledgements
We acknowledge financial support from University of Bologna
(RFO). Donation of chemicals from Dr Reddy’s Chirotech Tech-
nology Centre (Cambridge, UK) is gratefully acknowledged. F.H.
acknowledges financial support from the Gçran Gustafsson
Foundation and the Knut and Alice Wallenberg Foundation.
S.S. acknowledges financial support through a Programma Gio-
vani Ricercatori “Rita Levi Montalcini” fellowship. We are grate-
ful to Prof. Carmen Nàjera for a gift of (R)-BINOL and to Prof.
Giovanni Piersanti for useful discussion.
To increase the synthetic utility of this methodology, we
thought to convert one of the ketone groups of compounds 3
into a more versatile ester group. However, all attempts to
effect a Baeyer–Villiger oxidation on 3e failed, presumably due
Keywords: asymmetric synthesis · Brønsted acids · indoles ·
nitroalkenes · organocatalysis
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Communication
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ketone during the cyclization.
[19] The lowest energy pathway represented in Figure 2 leads to the forma-
tion of product trans-3. We also computed the pathway leading to the
cis isomer, and we found it to be associated with higher energy barriers
(see the Supporting Information), in agreement with the experimental
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undesired 3’ to tricyclic 3. Thus, the nitronate “quench” is an irreversible
process. Phosphoric acid-catalyzed direct additions proceeding through
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[20] We have also optimized the corresponding transition states for the re-
action occurring on the ester-substituted indole 1b that, when subject-
ed to reaction conditions, only afforded product 3’b. In this case, the
barriers for the formation of the two products are closer in energy,
mainly due to an increase in the energy required for the cyclization.
The calculations, however, still predict the preferential formation of the
cyclization product 3b, in disagreement with the experiments. This
could be an indirect proof that the barriers that we found for the tauto-
merizations giving the open-chain products 3’a or 3’b are slightly over-
estimated. Based on the experimental outcome of the reactions and on
the calculated barriers for the cyclizations affording 3a or 3b, a more
realistic value for the energy barriers of the tautomerization step lies
between 13 and 18 kcalmolÀ1. For additional discussion, see the Sup-
porting Information.
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[17] TS1’ evolves to intermediate INT1’, in which the anionic catalyst coordi-
nates the nitronic acid and the C3ÀH of the indole (see the Supporting
Published online on October 21, 2015
Chem. Eur. J. 2015, 21, 17578 – 17582
www.chemeurj.org
17582 ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim