Glutarimide Alkaloids Through Multicomponent Reaction Chemistry

Article abstract of DOI:10.1002/ejoc.201801276

A concise four step synthetic route for glutarimide alkaloids of high biological interest is presented. The scaffold is accessed via an Ugi four component reaction, hereby introducing two points of variation. This is followed by a hydrolysis, a cyclization under mild conditions, and an amine deprotection. The diastereomers of the cyclized intermediate can be easily separated, thus leading to optically pure alkaloids. By this route, four natural products and ten derivatives were synthesized. The scope and limitations of the synthetic methodology were investigated.

Full text of DOI:10.1002/ejoc.201801276

A Journal of
Accepted Article
Title: Glutarimide Alkaloids through Multi-Component Reaction
Chemistry
Authors: Markella Konstantinidou, Katarzyna Kurpiewska, Justyna
Kalinowska-Tłuscik, and Alexander Doemling
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801276
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801276
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10.1002/ejoc.201801276
European Journal of Organic Chemistry
COMMUNICATION
Glutarimide Alkaloids through Multi-Component Reaction Chemistry
Markella Konstantinidou,[a]Katarzyna Kurpiewska,[b]Justyna Kalinowska-Tłuscik,[b]and Alexander
Dömling*[a]
Dedication: to the 80th birthday of Nobel laureate RobertHuber
julocrotine.
Abstract: The concise four step synthetic route for glutarimide
alkaloids of high biological interest is presented. The scaffold is
accessed via an Ugi four component reaction, hereby introducing
two points of variation. This is followed by a hydrolysis, a cyclization
under mild conditions and an amine deprotection. The diastereomers
of the cyclized intermediate can be easily separated, thus leading to
optically pure alkaloids. Via this route, four natural products and ten
derivatives were synthesized. The scope and limitations of the
synthetic methodology are investigated.
For this aim, we employed multi-component reaction (MCR)
chemistry, which allows the effective synthesis of complex
scaffolds in a few steps having as starting point easily
14,15,16
accessible and diverse building blocks.
Multi-component
reaction products are easily amenable and tolerate a significant
amount of functional groups and by post-modifications can lead
to diverse and complex scaffolds.17,18
Introduction
The glutarimide moiety (2,6-piperidinedione) is present in a
number of natural product scaffolds and is linked to diverse
biological activities.In medicinal chemistry, the glutarimide
scaffold is present in derivatives with antibiotic,1 antiviral,2,3 anti-
inflammatory4 and neuroregenerative properties.5 Glutarimide –
containing polyketides have shown cell migration inhibitory
activity,6and glutarimide macroketones are effective against
cancer metastasis.7
Glutarimide alkaloids are an important class of natural products.
The scaffold is present in the structure of julocrotine, which has
shown antiproliferative effects in in vitro tests against the
promastigote
and
amastigote
forms
of
Leishmania
amazonensis.8
The structure of julocrotine was elucidated in 1961 with a series
of degradation reactions9 and a report in 1974 showed the
synthesis of a lower homologue using harsh conditions.10In
2011, a six step synthesis starting from L-glutamic acid was
described.11 Shortly afterwards, a four-step synthesis was
described starting from Cbz-glutamine. 12 In this case, the key
amine intermediate was used as the amine component of an Ugi
reaction, but with limited diversity. Moreover, a stereoselective
synthesis for julocrotine and structurally related glutarimide
alkaloids was reported based on Boc-L-glutamine.13(Figure 1)
Figure 1. Previous works and current approach.
Results and Discussion
Altogether, although the previously reported methodologies lead
to the desired natural products, they are restricted to the
synthesis of only one alkaloid and not allowing easily the
synthesis of derivatives. However, the establishment of a
convenient synthetic route for structurally related natural
products and derivatives is important for future pharmacological
studies, to evaluate the title compounds as a lead structure.
Thus, we envisioned an efficient synthetic route with variation
Retrosynthetically, the glutarimide scaffold can be accessed via
a 4-component Ugi reaction, followed by an intramolecular
cyclization (Scheme 1).
points, which was first established for the natural product
[a] M.Konstantinidou,Prof. A. Dömling
Drug Design, University of Groningen,
Scheme 1.Retrosynthesis
The aldehyde was synthesized in two steps by applying
previously described conditions with slight modifications; 19,20,21
first the opening of γ-butyrolactone towards methyl 4-
hydroxybutanoate, and then the oxidation to methyl 4-
oxobutanoate (Scheme 2).
Address Deusinglaan 1, 9713 AV Groningen, The Netherlands
E-mail: a.s.s.domling@rug.nl, homepage http://www.drugdesign.nl/
K. Kurpiewska, J. Kalinowska-Tłuscik
Faculty of Chemistry, Jagiellonian University
3 Ingardena Street, 30-060 Krakow, Poland
[b]
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Scheme 2. Aldehyde synthesis
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We found that the use of pyridinium chlorochromate (PCC)
resulted in much higher yields compared to the Swern oxidation.
Oxidation by Dess-Martin periodinane led to lower yields than
PCC and it was challenging to reproduce the same yields.
Moreover, with the ring opening approach, followed by the
oxidation with PCC, the aldehyde can be easily prepared at a
scale of 3 grams.
(R)-(+)-1-(4-methoxyphenyl)-ethylamine was used as a chiral
auxiliary which also can be easily deprotected on a later stage.
The overall synthetic route was established as a mild four step
synthesis starting from a four-component Ugi reaction. The
following table (Table 1) summarizes our optimization attempts
for the Ugi reaction.
Table 1.Optmiziation for the Ugi reaction
solvent concentration catalyst time,
heating
Yield[b]
1
2
3
4
5
6
MeOH
MeOH
TFE[a]
TFE
1M
1M
1M
1M
1M
1M
-
rt, 24 h
rt, 48 h
rt, 24 h
rt, 24 h
rt, 48 h
15%
35%
38%
24%
60%
-
-
ZnCl2
TFE
-
-
TFE
MW,100oC, 12%
1 h
7
TFE
2M
-
rt, 24 h
36%
Scheme 3.Synthetic route for natural julocrotine.
Conditions: (step 1) 2,2,2-trifluoroethanol (TFE), rt, 48 h, 1M,
(step 2) LiOH, MeOH – H2O 2:1, rt, 5 h, (step 3) (CH3CO)2O,
CH3COONa, reflux, 2 h, separation of diastereomers by column
chromatography, (step 4) TFA reflux, 24 h
[a] 2,2,2-trifluoroethanol (TFE), [b] isolated yield after column chromatography
The standard Ugi solvent methanol at room temperature
overnight, gave only a low conversion of 15%. Prolonging the
time at 48 h, increased the yield to 35%. An improvement was
observed with the use of 2,2,2-trifluoroethanol (TFE) as solvent.
However, the use of a Lewis acid (zinc chloride) as catalyst
considerably reduced the yield. Remarkably, heating the
reaction mixture in microwave conditions gave the lowest yield
of only 12%. Changing the concentration from 1M to 2M, had
almost no influence with yields of 38% and 36%, respectively.
The optimal conditions turned out to be TFE, 1M concentration,
The pivotal question was the assignment of the stereochemistry
for the final products. In order to determine the stereochemistry,
a crystal structure was solved for one of the diastereomers in the
cyclization step. This indicated that the isolated product
(compound 3c-ii) had (R,R,S) configuration. Thus, in order to
obtain the major diastereomer with the correct stereochemistry,
the synthesis was repeated with the (S)-(-)-4-methoxy-α-
methylbenzylamine auxiliary. The optical rotations of the final
product 3d-i and 3d-ii were the ultimate proof that the
stereochemistry is maintained in the deprotection step and that
the major product was the natural alkaloid julocrotine by using
the (S)-(-)-4-methoxy-α-methylbenzylamine auxiliary.
room temperature and 48
h reaction time. Under these
conditions 60% product was isolated.
With the optimized conditions in hand for the Ugi reaction, we
moved on to the next synthetic steps: an ester hydrolysis under
basic conditions (95% yield), followed by the intramolecular
cyclization with acetic anhydride and sodium acetate (74% yield
for the diastereomeric mixture). In the last step, the amine
protecting group is cleaved. (Scheme 3).
Next we were keen to apply the same synthetic approach to the
structurally related natural products crotonimides A, B and C.
22,23,24For these three alkaloids the amino-component was the
(S)-(-)-4-methoxy-α-methylbenzylamine auxiliary, whereas the
carboxylic acids were propionic acid for crotonimide A, isobutyric
acid for crotonimide B and benzoic acid for crotonimide C
(Scheme 4).
From the Ugi reaction, a new chiral center is introduced; thus
diastereomers are formed. The diastereomers can be separated
easily after the cyclization step bycolumn chromatography (in 3c
the diastereomeric ratio was 3:2, after separation with column
chromatography). In the last step, the cyclized products were
deprotected separately to yield the natural julocrotine 3d-i and
its diastereomer 3d-ii. The initial attempt to deprotect 3c-i by
hydrogenation on Pd/C was unsuccessful, but deprotection by
refluxing with TFA resulted in quantitative yield of 3d-i.
Scheme 4.Structures of julocrotine and crotonimides A, B, C.
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It is well-established that the Ugi reaction is not very
stereoselective. However, it is noteworthy that the
diastereomeric ratios (S,S) : (R,S) as determined by separation
in the cyclization step varied significantly. Even the reverse of
the ratio (S,S) : (R,S) of 4:5 and 3:2 was observed for
crotonimide A and B. The greatest difference was observed for
crotonimide C with a ratio (S,S) : (R,S) of 1:5. Thus the natural
product in this case was the minor formed diastereomer (Table
2). Although the route is not diastereoselective, the four natural
products could be synthesized with the same approach and the
diastereomers were easily separated after the cyclisation step.
Finally, optically pure compounds were obtained for the four
natural products, which is an advantage for potential biological
screening, since different enantiomers might cause different
biological effects. To the best of our knowledge, this is the first
report for the synthesis of both enantiomers for these three
glutarimide alkaloids (crotonimides A,B and C).
Scheme 5. Structures of the glutarimide natural product inspired
library components.
Table 2.Isolated yields and diastereomeric ratios (step 3) for the
natural products.
Natural
product
Step 1[a]
Step 2[a]
Step 3[a][b]
Step 4[a]
those cases were observed with 4-methyl-phenyl-isocyanide
12a (36%) and the bulky 4-biphenyl-isocyanide10a (37%).
Electron withdrawing groups on the benzyl isocyanide such as
bromo for 9a and cyano for 11a resulted in 50% and 40% yield,
respectively. The electron donating 3,4-dimethoxy group on the
benzyl isocyanide of 8a gave the desired product with 52%
yield. The bigger variations were observed for the derivatives
14a, 15a and 16a, which had the phenyl-ethyl isocyanide and
aromatic carboxylic acids. The higher yield was observed with
the 2-pyridine carboxylic acid 15a (41%), whereas the 2-
benzofuran 14a and the meta-bromo-benzoic acid 16a gave
only 24% and 29% yields, respectively. In the hydrolysis step
the yields ranged from quantitative to 65%, in the cases of
derivatives 15b (2-pyridine carboxylic acid) and 16b (meta-
bromo-benzoic acid).The yields in the cyclization step varied
significantly from 17% to 94%. Regarding the carboxylic acid
variations in the cyclization step, the yields were moderate
(benzofuran-2-carboxylic acid 14c (46%), pyridine-2-carboxylic
acid 15c (55%), acetic acid 7c (62%), cyclohexane-carboxylic
acid 13c 67%), with the exception of meta-bromo-benzoic acid
16c (17%). The isocyanide variation in the same step resulted in
moderate yields in the cases of the 3,4-dimethoxy-benzyl-
isocyanide 8c (20%) and the 4-methyl-phenyl-isocyanide 12c
(31%). On the contrary, the yields were high in the cases of 4-
bromo-benzyl-isocyanide 9c (52%), 4-biphenyl-isocyanide 10c
(72%) and 4-cyano-phenyl-isocyanide 11c (94%). The final acid-
mediated deprotection was performed in high yields in all cases
(70-98%).
julocrotine
60% (3a)
95% (3b)
74%(combined)
(3c-i):(3c-ii)
2:3
96% (3d-i)
83% (3d-ii)
crotonimide
A
52% (4a)
99% (4b)
41%(combined)
(4c-i):(4c-ii)
5:4
82% (4d-i)
90% (4d-ii)
crotonimide
B
52% (5a)
55% (6a)
95% (5b)
85% (6b)
53%(combined)
(5c-i):(5c-ii)
2:3
90% (5d-i)
82% (5d-i)
crotonimide
C
45%(combined)
(6c-i):(6c-ii)
1:5
90% (6d-i)
93% (6d-i)
[a] isolated yields, [b]diastereomeric ratios were determined after separation
with column chromatography
Next, we went on with the synthesis of a small compound library
in order to further explore the scope and limitations of this
synthetic approach. The initial Ugi four-component reaction
offers two points of variation: the carboxylic acid and the
isocyanide component. The aldehyde was kept constant to
afford 6-membered glutarimides. To investigate the scope and
limitation, 10 derivatives were synthesized by using the(R)-(+)-1-
(4-methoxyphenyl)-ethylamine and varying either the carboxylic
acid or the isocyanide (Scheme 5).
Limitations of the methodology were noted in the cases of
adamantyl- and indole substituents. The use of 1-adamantyl-
isocyanide resulted in the Ugi and saponification products as
expected. However, in the cyclization step only unreacted
starting material was obtained, likely due to sterical hindrance.
Furthermore, the use of the indole moiety, either as carboxylic
acid or isocyanide component, resulted into complicated
reaction mixtures in the Ugi reactions. The obtained products
could not be used further due to very low purity.
The cyclization products were deprotected as combined (S and
R mixtures with unspecified ratio) or diastereomeric mixtures,
although it would have been possible to separate the
diastereomers in the cyclization step with column
chromatography if necessary for future biological screening.
The isolated yields for the Ugi reaction varied from 24% to 53%
(Table 3). For the natural products 3a, 4a, 5a, 6a and derivatives
7a and 13a, which all had the phenyl-ethyl isocyanide and
different aliphatic carboxylic acids (either linear or cyclic) the
yields ranged from 52 to 60%. Derivatives 8a, 9a, 10a, 11a and
12a based on (S)-(+)-2-methyl-butyric acid and variable
isocyanides gave yields from 36 to 50%. The lowest yields in
An interesting observation was done when using meta-bromo-
benzoic acid. In the cyclization step only one diastereomer
(16c) was observed (as indicated by NMR data), which was
20
D
deprotected towards an enantiomer with optical rotation of [a]
=
+13.57 (c= 0.84, CHCl3) (16d). Although the optical rotation and
NMR data are not sufficient for determining the absolute
configuration of the product, this unexpected result seems to be
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10.1002/ejoc.201801276
European Journal of Organic Chemistry
COMMUNICATION
in agreement with the data from crotonimide C, where the again
aromatic benzoic acid component induced a high ratio (S,S) :
Table 3.Isolated yields for derivatives
Step 1[a]
Step 2[a]
Step 3[a][b]
Step 4[a][b]
Conclusions
Structure
Overall, we have established a mild multi-component synthetic
approach for glutarimide alkaloids, allowing the straight forward
synthesis of derivatives. The methodology was used for the
successful synthesis of four optically pure natural products. The
53%
(7a)
98%
(7b)
62%
(7c)
85%
(7d)
scope and limitations for
a small library synthesis were
examined and the stereochemistry was investigated. By our
synthetic route, the biological evaluation of the glutarimide
alkaloid scaffold will be significantly facilitated in the future.
52%
(8a)
80%
(8b)
20%
(8c)
75%
(8d)
Experimental Section
50%
(9a)
78%
(9b)
52%
(9c)
98%
(9d)
Procedure A: General procedure for the Ugi reaction. In a round
bottom flask, 2,2,2-trifluoroethanol (TFE, 1M) was added, followed by the
addition of the aldehyde (1equiv.) and the amine (1equiv.). After 30 min
of stirring in rt, the carboxylic acid (1equiv.) and the isocyanide (1equiv.)
were added. The reaction mixture was stirred at rt for 48 h. Then, the
solvent was removed under reduced pressure and the crude reaction
mixture was purified by column chromatography (GRACE, eluent: PE –
EA [0 to 100% EtOAc in PE]). For natural products, the scale was
4mmol, whereas for derivatives the scale was 1.5mmol.
37%
(10a)
90%
(10b)
72%
(10c)
77%
(10d)
40%
(11a)
86%
(11b)
94%
(11c)
70%
(11d)
Procedure B: General procedure for the hydrolysis. The Ugi product
(1equiv.) was dissolved at rt in a mixture of MeOH – H2O (2:1, 10ml for
1mmol of starting material). LiOH (1.5 equiv.) was added as solid. The
reaction mixture was stirred at rt for 5 h. Then methanol was removed
under reduced pressure. The residue was diluted with water (50ml) and
extracted with ethyl acetate (x2). The basic aqua phase was cooled in an
ice-bath and was acidified with 2N HCl, followed by an extraction with
ethyl acetate (50ml x 3). The combined organic phases were dried over
MgSO4 and the solvent was removed under reduced pressure.
36%
(12a)
96%
(12b)
31%
(12c)
82%
(12d)
Procedure C: General procedure for the cyclization. The carboxylic
acid (1equiv.) was dissolved in acetic anhydride (5ml for 1mmol of
starting material). Sodium acetate (1.2equiv.) was added as solid. The
reaction mixture was heated to reflux and the reaction was monitored by
TLC PE:EA 1:1. After 2h, it was allowed to reach rt. Then the reaction
mixture was cooled in an ice-bath and water was added. Extraction with
DCM (50ml x 2). The organic layers were dried over Na2S04 and the
solvent was removed under reduced pressure. The dark brown residue
was purified by column chromatography (PE:EA [0 to 100% EtOAc in
PE]). For the four natural products, diastereomers were separated during
the purification, whereas for the 10 derivatives no separation was
attempted.
55%
(13a)
82%
(13b)
67%
(13c)
90%
(13d)
24%
(14a)
97%
(14b)
46%
(14c)
89%
(14d)
Procedure D: General procedure for the deprotecion. The cyclized
product was dissolved in TFA (for 1mmol 10ml). The reaction mixture
was stirred at rt for 10min and then overnight reflux under tube of CaCl2
drying tube. The reaction mixture turned red. After 24 h it was allowed to
reach rt. Addition of 30ml of DCM and evaporation under reduced
pressure. The red residue was diluted with ethyl acetate (50ml) and was
washed with sat. NaHCO3 (50ml x3). The organic layer was dried over
MgSO4 and solvent was removed under reduced pressure to get a brown
residue, which was purified by column chromatography.
41%
(15a)
71%
(15b)
55%
(15c)
85%
(15d)
29%
65%
17%
90%
(16a)
(16b)
(16c)
(16d)
Crystallographic data have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no.
CCDC 1590022. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax:
+44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
[a] isolated yields, [b]stereoisomeric mixture (combined or diastereomeric
mixtures)
(R,S) of 1:5.
Conflict of interest
The authors declare no conflicts of interest.
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[24] B. Ndunda, M.K. Langat, J.M. Wanjohi, J.O. Midiwo, L.O. Kerubo,
Planta Med. 2013, 79, 1762 – 1766.
Acknowledgements
This research was supported to (AD) by the National Institute of
Health (NIH) (2R01GM097082-05), the European Lead Factory
(IMI) (grant agreement number 115489), the Qatar National
Research Foundation (NPRP6-065-3-012). Moreover funding
was received through ITN “Accelerated early stage drug
discovery” (AEGIS, grant agreement No 675555) and,
COFUNDsALERT (grant agreement No 665250) and Prominent
(grant agreement No 754425) and KWF Kankerbestrijding grant
(grant agreement No 10504).The research was carried out with
the equipment purchased thanks to the financial support of the
European Regional Development Fund in the framework of the
Polish Innovation Economy Operational Program (contract no.
POIG.02.01.00-12-023/08).
Keywords: alkaloids• MCR chemistry• glutarimide• natural
products • Ugi reaction
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Key Topic* alkaloids, MCR chemistry
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Tłuscik,[b]and Alexander Dömling*[a]
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Title Glutarimide Alkaloids through
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A mild four-step synthetic methodology for glutarimide alkaloids was established, based on the Ugi 4-component reaction. Four
natural products were synthesized, followed by the synthesis of a small library of derivatives. Stereochemistry, scope and limitations
of the methodology were investigated.
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