Application of a One-Pot Friedel–Crafts Alkylation/Michael Addition Methodology to the Asymmetric Synthesis of Ergoline Derivatives

Article abstract of DOI:10.1002/ejoc.201701480

Herein, we report a short and facile stereoselective route to ergoline derivatives. The key steps are a one-pot Friedel–Crafts alkylation/Michael addition sequence which, in the absence of chiral ligands, affords the trans-trans-stereoisomer in 44 % yield

Full text of DOI:10.1002/ejoc.201701480

A Journal of
Accepted Article
Title: Application of a One-Pot Friedel-Crafts Alkylation/Michael
Addition Methodology to the Asymmetric Synthesis of Ergoline
Derivatives
Authors: Christina Despotopoulou, Sean McKeon, Robert Connon,
Vincent Coeffard, Helge Müller-Bunz, and Patrick Jerome
Guiry
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10.1002/ejoc.201701480
European Journal of Organic Chemistry
COMMUNICATION
Application of a One-Pot Friedel-Crafts Alkylation/Michael
Addition Methodology to the Asymmetric Synthesis of Ergoline
Derivatives
Christina Despotopoulou,[a] Sean C. McKeon,[a] Robert Connon,[b] Vincent Coeffard,[a]† Helge Müller-
Bunz[a] and Patrick J. Guiry[a],[b],
*
Abstract: Herein, we report a short and facile stereoselective route to
ergoline derivatives. The key steps are a one-pot Friedel-Crafts
alkylation / Michael addition sequence which, in the absence of chiral
ligands, affords the trans-trans-stereoisomer in 44% yield as a
racemate. Screening of a range of chiral bisoxazoline ligands allowed
this sequence to proceed in 42-55% yields (six examples), with up to
99% ee. This approach allows for the first time, substitution at the C4-
position and the introduction of 3 chiral centres in one pot. An
interesting, base-mediated conversion of the trans-trans-
stereoisomer to the cis-cis-stereoisomer was discovered and both
stereoisomers were characterized by X-ray crystallography.
In recent years, ergot alkaloids with dopaminomimetic properties
attracted significant interest because of their potential to treat
neurological and endocrine disorders.2 The ergoline skeleton is
therefore an attractive building block for medicinal chemistry
research programs and is present in some leading
pharmaceuticals, such as the anti-Parkinson agents Lisuride (2)
and Pergolide(3).3
As a result, there is a requirement to develop new methods for the
synthesis of functionalised ergoline derivatives.4 The industrial
synthesis of the most important commercial ergot alkaloids starts
from naturally occurring lysergic acid obtainable by fermentation.
Lysergic acid already contains the full ergoline skeleton and the
carboxylic acid substituent from which a wide array of derivatives
can be prepared. However, use of this starting material does not
allow the introduction of substituents at the C4-position in the
ergoline scaffold. The synthesis of ergoline derivatives not
employing a semi-synthesis approach has not been extensively
studied to date and those that have been reported involve multi-
step syntheses.5
Ergot alkaloids exhibit a spectrum of structural diversity, biological
activity and therapeutic uses.1 To date, more than 40 ergot
alkaloids have been isolated from natural sources and they are
mainly produced by ascomycetes fungi of the Claviceps genus,
growing as parasites of rye, grass and cereals. The common
structural element is the tetracyclic ergoline ring system 1 (Fig. 1),
which bears
a
structural relationship to indole- and
catecholamines. As a result, ergot derivatives exhibit high levels
of affinity for recognition sites for serotonin, noradrenaline and
dopamine.
In 2015, Bernardi and co-workers developed an
organocatalysed tandem Friedel-Crafts alkylation/Michael
addition to synthesise the tricyclic core of the ergoline scaffold
Figure 1. The ergoline skeleton (1), present in the two anti-Parkinson drugs
Lisuride (2) and Pergolide (3).
[a]
Dr. C. Despotopoulou, Dr.S. McKeon, Dr. V. Coeffard, Dr. H. Müller-
Bunz and Prof. P. Guiry.
Centre for Synthesis and Chemical Biology
University College Dublin
Belfield, Dublin 4, Ireland.
E-mail: p.guiry@ucd.ie
[b]
Mr. R. Connon and Prof. P. Guiry
Synthesis and Solid State Pharmaceutical Centre (SSPC)
School of Chemistry, University College Dublin
Belfield, Dublin 4, Ireland
†
Dr. V. Coeffard – Present Address
Laboratoire CEISAM - UMR CNRS 6230, UFR des Sciences et
Techniques, 2 rue de la Houssinière - Bâtiment 22, BP 92208,
44322 Nantes Cedex 3 - France
Scheme 1. Previous Report and This Work
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10.1002/ejoc.201701480
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COMMUNICATION
from 4-substituted indole derivates and nitroethene (Scheme 1a).6
This methodology allowed for the installation of two contiguous
chiral centres at the C5- and C6-positions, but not the C4-position.
adduct 11d in 30 and 34%, respectively, and the cyclized product
12d-a in 16 and 17%, respectively, entries 1 and 2. The use of
THF gave an improvement in conversion to 11d and 12d-a of 46
and 20%, respectively, entry 3. Using CH2Cl2 as a solvent led to
an overall lower conversion compared to THF, giving 11d and
12d-a in 31 and 21%, respectively, entry 4. Finally, employing
CHCl3 as a solvent gave the best result, giving 11d and 12d-a in
44 and 25%, respectively, entry 5.
Herein, we report a related approach to access ergoline
derivatives of type 12 in only three steps, with complete
stereochemical control of three contiguous stereocentres (C4-C6).
The key step in this synthesis is a Zn(II)-catalyzed Friedel-Crafts
alkylation/Michael addition sequence (Scheme 1(b)).
During further optimization studies, we determined that 20
mol% of zinc triflate was sufficient to convert all of the starting
material. Performing the reaction in anhydrous CHCl3 at 40 °C,
led to full conversion of 9d into the desired precursor 11d, as well
as traces of the ergoline skeleton 12d-a in 48 h.
Our approach proposes to begin with easily accessible 4-
bromoindoles of type 7, the substrate for the Pd-catalyzed Heck
reaction with methyl acrylate 8 to afford the desired Michael-
acceptor 9. A Friedel-Crafts alkylation between indole 9 and trans-
-nitrostyrene 10 would give the ergoline precursor 11. Finally, an
intramolecular Michael addition would furnish the ergoline
derivative 12 that bears for the first time a substituent at the C4-
position. Commercially available 4-bromoindole 9a was coupled
via a Heck reaction with methyl acrylate 8 to form -unsturated
ester 9a in 85% yield, allowing us to then investigate the proposed
Friedel-Crafts alkylation (Scheme 2).
Table 1. Solvent Screen
Entry
Solvent
Toluene
Et2O
Conv. 11d[a]
30%
Conv. 12d[a]
16%
1
2
3
4
5
34%
17%
THF
46%
20%
CH2Cl2
CHCl3
31%
21%
44%
25%
[a] Determined from the 1H NMR spectrum of the crude product
However, by adding a base we aimed to promote the
intramolecular Michael addition to furnish 12d-a in a one-pot
procedure. Therefore, after completion of the Friedel-Crafts
alkylation step,9 the reaction mixture was cooled to 0 °C and an
equivalent of DBU was added.10 We were pleased to find that the
desired C4-substituted ergoline skeleton 12d-a was isolated in a
one-pot, two-step reaction in 55% yield under these reaction
conditions (Scheme 3).
Scheme 2. One-Pot Friedel-Crafts Alkylation/Michael Addition.
Zinc triflate was chosen as the Lewis acid as it has
consistently shown to be the best metal in terms of catalytic
activity and asymmetric induction for this type of reaction with the
bisoxazoline class of chiral ligands.7 However, when performing
the Friedel-Crafts reaction, we observed not only the expected
Friedel-Crafts adduct 11a (38%), but also the desired tricyclic
ergoline skeleton 12a (10%).
However, 12a proved to be unstable at room temperature and
we therefore screened several different protecting groups starting
from the corresponding N-protected 4-bromoindole.8 The tosyl-
and benzyl-protected indoles 9b and 9c, respectively, failed to
undergo the one-pot Friedel-Crafts/Michael addition sequence.
Finally, the N-methylated indole 7d was converted in to the -
unsturated ester 9d, an intermediate that formed a stable ergoline
precursor of type 12d-a. In order to find optimal reaction
conditions for the conversion of 9d and 10a into 12d-a, a solvent
screen was carried out at room temperature with 5 mol% zinc
triflate for 24 hours, table 1. Reactions in oluene and diethyl ether
provided moderate conversions affording the Friedel-Crafts
Scheme 3. Optimised Conditions for the Synthesis of Ergoline Analogue 12d-
a.
With this Friedel-Crafts/Michael addition sequence we managed
in one pot to create three contiguous stereocenters, thus
potentially forming 8 stereoisomers and 4 enantiomeric pairs A-D
(Fig. 2). The pair of enantiomers A that is sterically most
favourable, representing the trans-trans-configuration, was
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10.1002/ejoc.201701480
European Journal of Organic Chemistry
COMMUNICATION
formed in excess and was isolated by column chromatography in
44% yield. Enantiomeric pairs B-D were isolated as a mixture in
11% yield.
At this point, using a weaker base to set up an equilibrium away
from the favoured major diastereomer seemed fruitless, so we
turned our attention to the use of strong non-nucleophilic bases.
Gratifyingly, the reaction of 12d-a-A with NaH, followed by an
NH4Cl (aq.) quench, led to the isolation of 12d-a-C in 60% yield
from a 2:1 mixture of 12d-a-A and 12d-a-C (Scheme 4). This was
analysed by X-ray crystallography to prove the relative
stereochemistry of the substituents as cis-cis (Fig. 4).
Figure 2. Enantiomeric pairs A, B, C, and D of ergoline precursor 12d-a..
Figure 4. Crystal structure of enantiomeric pair C of compound (±)-12d-a.
Thermal ellipsoids are drawn on the 50% probability level.
The major enantiomeric pair A was also analysed using X-ray
crystallography, which proved the relative orientation of the
substituents (Fig. 3).
Having established the conditions for the one-pot/two-step
reaction that forms the 3 stereogenic centers, we then proceeded
to perform the reaction asymmetrically. Bisoxazoline ligands have
proven in the past very successful in the Friedel-Crafts alkylation
of indoles12 and were therefore employed in our reaction
sequence (Scheme 5).
.
Figure 3. Crystal structure of enantiomeric pair A of compound (±)-12d-a.
Thermal ellipsoids are drawn on the 50% probability level.
With a racemic synthesis of the major enantiomeric pair A1-A2,
representing the trans-trans diastereomers, in hand, we set out to
develop
a method to access other diastereomers. We
hypothesized that the high acidity of the nitro-group -proton (pKa
~ 10)11 would allow us to isomerize diastereomer A by using the
appropriate base. We started with the organic amine bases Et3N
and DBU, which resulted in no reaction and degradation of 12d-
a-A respectively.
Scheme 5. Screen of Different Bisoxazoline Ligands in the One-Pot Friedel-
Crafts Alkylation/Michael Addtion.
Their effect was always tested on the major enantiomeric pair A
that could be isolated. Initial screening, of a number of different
monosubstituted bisoxazoline ligands of type 13, led to only
moderate ee’s. However, employment of the symmetrical
disubstituted bisoxazoline ligand 14 gave, in the case of trans-β-
nitrostyrene 10a, the tricyclic product 12d-a-A in 53% yield and in
99% ee.
The one-pot/two-step reaction was repeated under these
optimized conditions, employing ligand 14, with a number of
commercially available nitrostyrenes 10a-f in order to vary the Ar
groups at the C4 position of the ergoline skeleton, Table 1.
Scheme 4. Base-Mediated Isomerization of 12d-a-A.
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Introducing a substituent on the aryl ring of the nitrostyrene
affected the enantioselectivities significantly. Performing the
reaction with 4-methylphenyl-nitrostyrene (10b), ergoline
derivative 12d-b was formed in 55% yield and in an ee of 62%
(entry 2), while nitrostyrene 10c, bearing a para-chlorophenyl
afforded 12d-c in 48% yield and 68% ee (entry 3). Having a para-
methoxy substituent on the aryl ring as in styrene 10d was not
beneficial as product 12d-d was isolated in 42% yield, while the
ee of the major enantiomeric pair was 44% (entry 4). Contrary to
the para-substituted aryl nitrostyrenes, meta-substituted styrenes,
gave better enantioselectivities. Reacting meta-chlorophenyl
nitrostyrene (10e) with indole 9d, ergoline derivative 12d-e was
isolated in 50% yield and 84% ee. Replacing the chlorine with
bromine in nitrostyrene 10f afforded 12d-f in 49% yield and 75%
ee.
in acetic acid and MeOH. Reduction of the nitro group was
followed by direct attack on the ester functionality and the desired
lactam 15 was formed in one pot in 61% yield.
In conclusion, we have developed a short and facile
stereoselective synthesis of ergoline derivatives, by employing a
one-pot/two-step Friedel-Crafts/Michael addition sequence. In
addition, we were able to introduce, for the first time, variable
substituents at the C4-position of the ergoline scaffold, a feature
that opens possibilities of producing a broad range of new
interesting ergoline analogues. Furthermore, we could control the
3 chiral centers formed in one step, by employing a bisoxazoline
ligand with an optimal ee value of 99%. Finally, our approach is
complementary to Bernardi’s and makes this sequence suitable
for the fast creation of a library of ergoline analogues to be used
for biological evaluation.
Table 2. Substrate Scope
Acknowledgements
We acknowledge award of a Postdoctoral scholarship for C.D.
funded by Higher Education Authority’s PRTLI Cycle 4 and
Science Foundation Ireland for a postdoctoral fellowship for V.C.
and a PhD scholarship for S.McK. (054/RFP4/CHE/0075). This
publication has also emanated from research conducted (RC)
with the financial support of the Synthesis and Solid State
Pharmaceutical Centre, funded by Science Foundation Ireland
(SFI) under Grant No. 12\RC\2275) and is co-funded under the
European Regional Development Fund under Grant
Number 14/SP/2750. We acknowledge facilities provided by the
Centre for Synthesis and Chemical Biology (CSCB) funded by the
Higher Education Authority’s PRTLI. We thank Dr Yannick Ortin
(NMR spectroscopy), Dr Jimmy Muldoon and Kevin Conboy
(mass spectrometry) and Ms Ann Connolly (microanalysis) for
technical support.
Entry
Ar
Ph
Tol
10
12d
Yield
53
ee[a]
99 (A2)
62
1
2
10a
10b
12d-a-A
12d-b
55
3
4
5
6
p-Cl-C6H4
p-OMe-C6H4
m-Cl-C6H4
m-Br-C6H4
10c
10d
10e
10f
12d-c
12d-d
12d-e
12d-f
48
42
50
49
68
44
84
75
Keywords: Ergolines • Asymmetric Synthesis • Friedel-Crafts
Alkylation • Michael Addition
[a] The major enantiomer was determined by comparison of
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