Synthesis of (-)-julocrotine and a diversity oriented Ugi-approach to analogues and probes

Article abstract of DOI:10.3762/bjoc.7.175

An improved total synthesis of (-)-julocrotine in three steps from Cbz-glutamine, in 51% overall yield, is presented. To demonstrate the potential of the heterocyclic moiety for diversity oriented synthesis, a series of (-)-julocrotine analogues was synthesized by employing the heterocyclic precursor as an amino input in Ugi four-component reactions (Ugi-4CR) [1].

Full text of DOI:10.3762/bjoc.7.175

Synthesis of (−)-julocrotine and a diversity oriented
Ugi-approach to analogues and probes
Ricardo A. W. Neves Filho1, Bernhard Westermann1,2
and Ludger A. Wessjohann*1,2,§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1504–1507.
1Department of Bioorganic Chemistry, Leibniz Institute of Plant
Biochemistry, Weinberg 3, 06120 Halle, Germany and
2Martin-Luther-University Halle-Wittenberg, Institute of Organic
Chemistry, Kurt-Mothes-Str. 2, 06120 Halle, Germany
doi:10.3762/bjoc.7.175
Received: 01 September 2011
Accepted: 21 October 2011
Published: 07 November 2011
Email:
Ludger A. Wessjohann* - wessjohann@ipb-halle.de
This article is part of the Thematic Series "Multicomponent reactions".
Guest Editor: T. J. J. Müller
* Corresponding author
§ Tel: +49 345 5582 1301; Fax: +49 345 5582 1309
© 2011 Neves Filho et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
diversity oriented synthesis; julocrotine; leishmania; Mitsunobu
reaction; Ugi reaction
Abstract
An improved total synthesis of (−)-julocrotine in three steps from Cbz-glutamine, in 51% overall yield, is presented. To
demonstrate the potential of the heterocyclic moiety for diversity oriented synthesis, a series of (−)-julocrotine analogues was
synthesized by employing the heterocyclic precursor as an amino input in Ugi four-component reactions (Ugi-4CR) [1].
Introduction
Julocrotine (1) is a natural glutarimide alkaloid isolated from In addition, the glutarimide motif can be considered as a
several plants of the genus Croton [2-4], including Croton privileged structure. Compounds with this pharmacophore
cuneatus Klotzsch, which is used by Amazonia natives in anti- often exhibit a wide range of biological properties including
inflammatory and analgesic medicines. The structure of this anti-inflammatory [10], antitumor [11,12], and anticonvulsive
glutarimide-containing alkaloid was first proposed in 1960, properties [13].
based upon a series of degradative experiments, but only
confirmed in 2008 by X-ray analysis [5-7]. Most interestingly, Because of the low yields of julocrotine obtained through
it was found to inhibit the growth of promastigote and isolation from natural sources and the necessity to gain access
amastigote forms of the protozoan Leishmania amazonensis (L.) to larger quantities of this substance for further biological
with no cytotoxicity against the host cell [8]. This parasite screening, Silva and Joussef developed a straightforward total
causes cutaneous leishmaniasis, a neglected disease that affects synthesis in six steps [14]. Starting from L-glutamic acid, their
more than 12 million people in tropical countries [9].
chiral-pool approach yielded the desired optically active natural
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product in 41% overall yield. After analyzing the structure of
(−)-julocrotine, we set out to synthesize it in only three steps
from commercially available L-Cbz-glutamine, in a sequence of
cyclization (a), N-alkylation (b), and the removal of the
protecting group followed by acylation with (S)-2-methylbu-
tanoic acid (c) [15] (Figure 1).
Scheme 1: Reactions and conditions: (a) DCC, NHS, DMF 80 °C,
18 h, 76%. (b) Ph(CH2)2Br, K2CO3, acetone, r.t., 20 h, (±)-4, 98%. (b')
Ph(CH2)2OH, DIAD, PPh3, THF, r.t., 20 h, (−)-4, 90%. (c) H2, 10% w/w
Pd/C, MeOH, r.t., 4 h, quant. (d) (S)-2-methylbutanoic acid, EDCl,
HOBt, CH2Cl2, r.t., 16 h, 73%.
Figure 1: Retrosynthetic scheme for (−)-julocrotine (1).
and tert-butyl isocyanide (Scheme 2). These analogues possess
a protease-resistant peptoid scaffold and this might lead to an
enhanced activity [19,20]. In this endeavor, all Ugi reactions
were initiated by pre-imine formation of 5 and reaction with
formaldehyde as the oxo-component, after which the multicom-
Based on this flexible route, we also envisioned the synthesis of
derivatives utilizing post-cyclization transformations by multi-
component reactions. This diversity-driven approach benefits
from the fact that the heterocyclic moiety may be considered a
privileged structural element for bioactivity.
Results and Discussion
The synthetic approach, illustrated in Scheme 1, starts from
Cbz-glutamine 2, which reacted in the presence of dicyclo-
hexylcarbodiimide (DCC) and N-hydroxysuccinimide (NHS) in
DMF to afford Cbz-glutarimide 3 in 76% yield in optically pure
form [16]. To alkylate the imide-moiety, glutarimide 3 was
reacted with phenylethyl bromide in the presence of potassium
carbonate at room temperature. The desired compound 4 was
obtained in 98% isolated yield, but analysis revealed racemiza-
tion. Indeed, the equilibration at the chiral center of 4 can be
observed even in the presence of weak bases such as potassium
carbonate [17]. Thus, we decided to use a base-free N-alkyl-
ation protocol, namely the Mitsunobu reaction of 3 and the
readily available 2-phenylethanol [18]. This protocol gave the
desired optically active product in 90% yield ([α]20D −29.2).
The key intermediate 4 was hydrogenated on Pd/C at room
temperature to afford 5, which was coupled with (S)-2-
methylbutanoic acid in the presence of EDCl and HOBt to
afford (−)-julocrotine (1) in 73% yield, over two steps. The
HRMS, 1H and 13C NMR spectra, optical rotation, and melting
point of 1 were consistent with the reported data [2,14,15].
For the diversity oriented synthesis the advanced intermediate 5
was used as the amino component in an Ugi-4CR with (S)-2-
methylbutanoic acid, hydrophobic amino acids, formaldehyde
Scheme 2: Reactions and conditions: (a) (CH2O)n, MeOH, r.t., 2 h
then, RCOOH and t-BuNC, r.t., 18 h.
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ponent reaction was completed by the addition of (S)-2-
methylbutanoic acid, Boc-Gly, Boc-Ala, Boc-Val, Boc-Leu,
Boc-Phe and Boc-Ile and tert-butyl isocyanide. Following this
procedure, the desired optically active compounds 6a–g were
obtained in 55–63% yields. Their structures were confirmed by
1H, 13C NMR and HRMS spectra.
Supporting Information
Supporting Information File 1
Experimental procedures and analytical data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-175-S1.pdf]
Finally, the Ugi-4CR was utilized for the synthesis of a molec-
ular probe prototype of 1, which can be used for intercalation
studies (Scheme 3). For this propose, the natural product scaf-
fold should be attached through a spacer to a reporter tag, which
is normally a luminescent group or a dye. The advanced inter-
mediate 5 was converted to the respective imine as depicted in
Scheme 2 and then reacted with (S)-2-methylbutanoic acid and
isonitrile 7 to afford the intermediate 8 in 61% yield. This com-
pound was then hydrogenated to afford 9 and then directly
coupled with 1-pyrenemethylamine, by using EDCl as coupling
reagent, to yield the designed probe prototype 10 in 80% yield
(from 8).
Acknowledgements
The authors thank Dr. Jürgen Schmidt and Mr. Torsten Geißler
for the HRMS and emission spectra and Ms. Leah M. Harris for
a kind revision of this manuscript. R.A.W.N.F. is grateful to
CNPq for a Ph.D. fellowship.
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Scheme 3: Reactions and conditions: (a) (CH2O)n, MeOH, r.t., 2 h then, (S)-2-methylbutanoic acid and 7, r.t. 18 h, 61%. (b) H2, 10% w/w Pd/C,
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