A benzotriazole-mediated route to protected marine-derived hetero-2,5-diketopiperazines containing proline

Article abstract of DOI:10.1039/c5ob00023h

A procedure for the cyclization of dipeptidoyl benzotriazolides containing proline derivatives promoted by triethylamine under MW activation is introduced. The reaction is general for a variety of dipeptidoyl benzotriazolides and represents a very practical and convenient method for the preparation of Pro- or Hyp-derived 2,5-diketopiperazines (2,5-DKPs) and bis-DKPs with a disulfide linker. This method can be used for the construction of 2,5-DKP compound libraries and for the synthesis of natural products with diketopiperazine cores. This journal is

Full text of DOI:10.1039/c5ob00023h

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A Benzotriazole-Mediated Route to Protected
Marine-Derived Hetero-2,5-Diketopiperazines
Cite this: DOI: 10.1039/x0xx00000x
Containing Proline†
Olivier Nsengiyumva,a Sadra Hamedzadeh,a James McDaniel,a Jocelyn Macho,a Grant
Simpson,a Siva S. Panda,a Khanh Ha,a Iryna Lebedyeva,a Hassan M. Faidallah,b Manal
Metgen AL-Mohammadi,b C. Dennis Hall,a,* and the late Alan R. Katritzkya,b#
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
procedure for the cyclization of dipeptidoyl molecules.13,14,15 It was also found that Gram-positive Lactobacillus
benzotriazolides containing proline derivatives promoted by plantarum species produced cyclic dipeptides, including cyclo( -Phe-
triethylamine under MW activation is introduced. The Pro), cyclo( -Phe-trans-4-OH- -Pro), and cyclo(Gly- -Leu), which
reaction is general for
variety of dipeptidoyl exhibited antifungal activity.16 In addition DKP, bearing a proline
benzotriazolides and represents
very practical and residue have proved to be useful as macrophage cytokines stimulators.1
convenient method for the preparation of Pro- or Hyp- Since the first isolation of a diketopiperazine (DKP) from the
derived 2,5-diketopiperazines (2,5-DKPs) and bis-DKPs with sponge Dysidea herbacea 17
there have been several reports describing
L
L-
L
L
L
a
a
,
a disulfide linker. This method can be used for the the isolation of this class of compounds from other marine sponges.17
construction of 2,5-DKP compound libraries and for the DKPs are also obtained from marine microbial sources, including the
synthesis of natural products with diketopiperazine cores.
Introduction
proteobacteria Alcaligenes faecalis, isolated from the sponge Stelletta
tenuis. The metabolites from these investigations contain 4-hydroxy-
proline, proline, phenylalanine, arginine , leucine, isoleucine, norvaline
or alanine (Figure 1).17
Hetero-2,5-diketopiperazines (2,5-DKPs) containing proline and
hydroxy-proline residues represent a unique class with important
characteristics in both structural detail and biological activity.1,2,3
Because of their important biological properties, it is important to
develop an efficient flexible, and cost-effective strategy for the
synthesis of these proline-based marine microbial metabolites. Although
general solid-phase methods for the synthesis of 2,5- DKPs containing
L-proline amino acid residue have been developed18 to produce
combinatorial libraries, these solid-phase reactions are all small in scale
and have limited use because of the problems associated with scaling
up of solid-phase reactions.3 Proline-derived DKPs can also be
synthesized via cyclization of the corresponding linear dipetide ester
precursor substituted with an amine at one terminus and an esters at the
other. Dipeptide esters can cyclize to form a 2,5-DKPs in the presence
of strong base.6,19,20 However, careful selection of the base and reaction
conditions are required to avoid racemization. Solution phase
methodologies for the synthesis of 2,5-DKP containing proline
A
common motif of marine-derived 2,5-DKPs is a proline-derived DKP-
backbone with an annulated ring system derived from a prenylated
tryptophan.4,5,6 The 2,5-DKP scaffold forms the core of many natural
product families such as brevianamide,7 okaramine8,9 and
spirotryprostatines10 and is thus an extremely interesting synthetic
target for the assembly of natural product-like libraries of high
pharmaceutical potential. Marine-derived proline-containing D,D-
diketopiperazines showed strong antibiotic activity against Vibrio
anguillarum.11 When used in combination, the two antimicrobial cyclic
dipeptides, cyclo(Leu–Pro) and cyclo(Phe–Pro), exhibit strong synergy
in inhibiting the growth of VRE and other pathogenic
microorganisms.12 A number of DKPs, including cyclo(
L-Tyr-L-Pro)
employed a route that utilized a N-protected α-amino acid and a α-
and cyclo(L-Phe-L-Pro), have been detected in culture supernatants
from a variety of Gram-negative bacteria, such as Pseudomonas spp.,
Vibrio spp., Proteus mirabilis, Citrobacter freundii, and Enterobacter
agglomerans, have been shown to modulate quorum-sensing systems
that commonly respond to acyl-homoserine lactone signaling
7,9,21,22
amino acid ester.
Deprotection of the dipeptide followed by
cyclization in situ forms the desired DKP molecule.4,9,23,24,25 Problems
were encountered during the deprotection/cyclization process,. For
example, removal of Cbz by hydrogenation resulted in over-reduction
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and removal of Fmoc with base caused epimerisation to yield a mixture Synthesis of protected marine-derived DKPs containing Pro. As
of diastereomers.8
outlined in Scheme 1, marine microbial metabolite cyclo-[ -Ala- -Pro-]
5a was selected as the first target. Compound 5a was synthesized in a
4-step procedure starting from 1a. Cbz-N-protected -Ala 1a was first
converted into the benzotriazolide 2a in 83% yield using a known
procedure.27,32 Reaction of 2a with
-Pro gave 3a, which was converted
D
L
D
L
into Cbz-dipeptidoyl benzotriazolide 4a.Treament of 4a under MW
activation at 100 oC in acetonitrile in the presence of triethylamine for
3 h, afforded crude 5a (Scheme 1): The major product was confirmed
as cyclic dipeptide cyclo-(Cbz-D-Ala-L-Pro) 5a by NMR. Protected
DKP 5a was then purified by gradient chromatography (DCM/hexanes)
to obtain the pure compound in 62 % isolated yield. (Table 1)
Figure
1
Representative of marine-derived hetero-2,5-diketopiperazines
containing proline.
Our longstanding involvement in benzotriazole (Bt)-mediated
oligopeptide chemistry26,27,28,29,30 prompted us to design a new, versatile,
and flexible strategy to provide these important marine-derived hetero-
2,5-DKPs containing proline and Hyp starting from inexpensive l,l-
dipeptidoyl benzotriazoles. In this project, we develop our cyclization
method31,32 on protected N-terminal for the synthesis of protected
marine-derived DKPs (Figure 2).
Scheme 1 Synthesis of protected marine-derived hetero-2,5-diketopiperazines
containing proline using benzotriazole auxiliary.
To prove the generality of our method, we studied the base/MW
activated cyclization reaction of Cbz-
cyclization of dipeptidoylbezotriazolide 4b was similar to compound 4a
and DKP cyclo-[Cbz- -Phe- -Pro] was obtained in 83% yield (Table 1,
Scheme 1). Next we paid attention to cyclo-[Cbz- -Ala- -Pro] 5c
D
-Phe-
L
-Pro-Bt 4b
.
The
D
L
D
D
,
whose unprotected analogue was isolated from marine bacteria
associated with cultures of Pecten Maximus.33 DD- DKPs showed
potent inhibitory activity against the pathogen V. anguillarum, superior
to that of the antibiotics actually in use in aquaculture such as oxytet-
racycline.33 Using our cyclization method, compound 5c was
synthesized in 79% yield from 4c (Table 1, Scheme 1).
Synthesis of protected DKPs containing Hyp. To broaden the
utility of the method, we applied our condensation procedure to the
cyclization of 4d-g for the synthesis of hydroxyproline (Hyp)-derived
DKPs 5d-g (Table 1 entries 4-7, Figure 2).
In sharp contrast to numerous studies dedicated to the synthesis and
biological properties of 2,5-DKPs containing Pro,13,14,34,35,36 relatively
few Hyp-derived DKPs have been reported.37,38,39Hyp can be
modified via "proline editing" to incorporate structured amino acid
mimetics (Cys, Asp/Glu, Phe, Lys, Arg, pSer/pThr) and recognition
motifs (biotin,RGD).40 Hyp editing at the 4-position provides access to
these proline derivatives which are valuable building blocks for drug
development. Cyclisation of linear peptide containing Hyp is
challenging due to the (predominant) trans arrangement of the amide
Figure 2 Synthetic strategies to form hetero-2,5-DKPs containing proline
Results and discussion
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Table 1 Synthesis of marine-derived hetero-2,5-diketopiperazines.
Entry
Amino acid 1
Cbz-D-Ala
Cbz-D-Phe
Cbz-D-Ala
Cbz-D-Ala
Cbz-D-Phe
Cbz-L-Leu
Cbz-L-Ile
Amino acid 2
L-Pro
Product
Yield (%)
1
2
3
4
5
6
7
cyclo-(Cbz-D-Ala-L-Pro) (5a)
cyclo-(Cbz-D-Phe-L-Pro) (5b)
cyclo-(Cbz-D-Ala-D-Pro) (5c)
cyclo-(Cbz-D-Ala-L-Hyp(Bn)) (5d)
cyclo-(Cbz-D-Phe-L-Hyp(Bn)) (5e)
cyclo-(Cbz-L-Leu-L-Hyp(Bn)) (5f)
cyclo-(Cbz-L-Ile-L-Hyp(Bn)) (5g)
62
83
79
70
80
76
82
L-Pro
D-Pro
L-Hyp(Bn)
L-Hyp(Bn)
L-Hyp(Bn)
L-Hyp(Bn)
Figure 2 Structure of of hydroxyproline (Hyp)-derived DKPs 5d-g.
bond in the linear Hyp precursor, preventing the correct spatial
positioning of the terminal amine and the activated carboxylic group
for cyclisation.41,42,43 Due to strong non-covalent interaction
between adjacent amide bonds through an n→π* interaction in the
C4-endopuckered C4-hydroxyproline, C4-OH substituted proline
prefers endo-ring pucker with trans amide bonds which prevents the
cyclization ring construction to form the 6-membered ring cyclic
obtained by direct modification of the N-alkylated DKP core via
carbanion chemistry46,47 or radical dimerization.48,49 However, these
procedures
have
limited
utility
because
multiple
protection/deprotection steps limit the methodology to specific
peptide sequences. To study the lactamization reaction to form
dimeric DKPs 10a
three-step procedure starting from cysteine or homo-cysteine
following the strategy used for compounds 4a (Scheme 2).
Cyclization of 9a occurred under conditions similar to those used
for the cyclization of 4a and gave the desired hyp-derived bis-
2,5-DKPs 10a in yields of 84% and 88% (Scheme 3).
,b, the starting materials 9a,b were obtained in a
dipeptide cyclo(-aa-
L
-Hyp-).
–g
To broaden the scope of our methodology,44 Hyp-derived 5d–g
,b
were considered as potential targets (Table 1, Figure 2). The
–g
macrolactamizations of Cbz-
Phe- -Hyp(Bn)-Bt 4e were initiated by treatment with TEA for 1–2
h in dry MeCN under MW activation. The protected Hyp-containing
trans-DKPs 5d were isolated in high purity after recrystallization.
A similar protocol was used to synthesize Hyp-derived cis-2,5-DKP
5f cyclo-(Cbz- -Leu- -Hyp(Bn)) (76%) and 5g (Cbz- -Ile- -Pro)
D-Ala-
L
-Hyp(Bn)-Bt 4d and Cbz-
D
-
,b
L
,
e
L
L
L
D
(82% ) by cyclization of its benzotriazolide precursors 4f and 4g
(Scheme 1, Table 1, Figure 2).
Bt Auxiliary Method for Synthesis of Symmetrical Hyp-
Derived Bis-2,5-DKPs. Next, we applied the procedure to the
cyclization of open chain peptidoyl benzotriazolides 9a
,
b
for the
synthesis of symmetrical dimeric DKPs 10a,b with a disulfide bond
linker (Scheme 2 and 3).
Literature examples of bis-DPKs include compounds endowed with
antagonist and anticancer activity.24 Naturally occurring bis-DPKs
chaetocin and chetomin are inhibitors of HIF-1α-p300/CBP
interaction, although the inhibition mechanism remains unclear.45
Comparative analysis has shown that bis-DKPs impact highly on
the expression level of hypoxia-inducible genes and have more
genome-wide effects than DKPs.46 Bis-2,5-DKPs can also be
Scheme 2 Synthesis of Bis-benzotriazoles 9a,b.
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Scheme 3 Cyclization of Bis-Cbz-dipeptidoyl Benzotriazoles 8a,b.
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Acknowledgments
We thank the University of Florida and the Kenan Foundation for
financial support. This paper was also supported by the NSTIP
strategic technologies program in the Kingdom of Saudi Arabia-
Project No. (12-ADV2732 - 03). The authors also, acknowledge
with thanks Science and Technology Unit, King Abdulaziz
University for technical support. The authors are grateful to Mrs.
Galyna Vakulenko, and Mr. Z. Wang for helpful discussions, to Dr.
M. C. A. Dancel (University of Florida, Mass Spectrometry
Services) for HRMS analysis. S. Hamedzadeh is grateful to UF-
HHMI Science For Life program for Intramural Undergraduate
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aCenter for Heterocyclic Compounds, Department of Chemistry,
University of Florida, Gainesville, FL 32611-7200, USA, Fax: 352-
392-9199; Tel: 352-392-0554, e-mail: charlesdennishall@gmail.com
bDepartment of Chemistry, King Abdulaziz University, Jeddah, 21589,
Saudi Arabia
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#Prof. A.R. Katritzky passed away 10th February 2014
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†Electronic Supplementary Information (ESI) available: Experimental
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