Synthesis of fluorescent (benzyloxycarbonylamino)(aryl)methylphosphonates

Article abstract of DOI:10.3762/bjoc.10.68

The synthesis of a library of structurally variable aromatic esters of (benzyloxycarbonylamino)(aryl)methylphosphonic acids is described by means of the Oleksyszyn reaction. The library was enlarged by the application of a Suzuki-Miayra approach and by preparation of mixed esters.

Full text of DOI:10.3762/bjoc.10.68

Synthesis of fluorescent
(benzyloxycarbonylamino)(aryl)methylphosphonates
Michał Górny vel Górniak1,2, Anna Czernicka1, Piotr Młynarz1,
Waldemar Balcerzak3 and Paweł Kafarski*1,2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 741–745.
1Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław
University of Technology, Wybrzeże Wyspiańskiego 27, 50-370
Wrocław, Poland, 2Department of Chemistry, University of Opole, pl.
Kopernika 11a, 45-040 Opole, Poland and 3First Department of
General, Gastroenterological and Endocrinological Surgery, Wroclaw
Medical University, ul. Marii Skłodowskiej-Curie 66, 50-369 Wrocław,
Poland
doi:10.3762/bjoc.10.68
Received: 04 December 2013
Accepted: 12 March 2014
Published: 28 March 2014
This article is part of the Thematic Series "Organophosphorus chemistry".
Guest Editor: P. R. Hanson
Email:
Paweł Kafarski* - pawel.kafarski@pwr.wroc.pl
© 2014 Górniak et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
aminophosphonates; Oleksyszyn reaction; organophosphorus;
Z-aminophosphonate esters
Abstract
The synthesis of a library of structurally variable aromatic esters of (benzyloxycarbonylamino)(aryl)methylphosphonic acids is
described by means of the Oleksyszyn reaction. The library was enlarged by the application of a Suzuki–Miayra approach and by
preparation of mixed esters.
Introduction
Screening of the activity of large libraries of fluorogenic Diaryl esters of α-aminoalkanephosphonic acids and their short
substrates of chosen enzymes is an emerging approach to deter- peptides are a class of well-established inhibitors of serine
mine their substrate preferences and thus to provide a set of data proteases [11,12]. Their mechanism of action involves phospho-
useful for the preparation of their selective inhibitors [1-5]. nylation of the active-site of these enzymes with simultaneous
Such fluorogenic probes have been also used for profiling the release of the appropriate phenol [13,14]. Therefore, the syn-
proteolytic secretomes with the obtained profiles being useful as thesis of such inhibitors carrying fluorescent probes in their side
diagnostic tools [6-8]. Also conjugates of drugs with fluores- chains or in the ester phosphonate moieties might find an appli-
cent probes have been used as so called theranostics (combina- cation in constructing fluorescent probes for studying structural
tion of therapeutics and diagnostics) [9,10].
requirements of enzymes having serine in their active sites
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Beilstein J. Org. Chem. 2014, 10, 741–745.
(proteinases and phosphatases) or to study their elevated level less satisfactory results because the obtained crude products
in various tissues. Thus, their libraries may serve for the were difficult to purify.
construction of diagnostic tools. A similar approach has been
recently patented as a mean to differentiate lipases and esterases The obtained phosphites were reacted with benzaldehyde and
[15].
benzyl carbamate, according to literature [18-20], providing the
desired diaryl (benzyloxycarbonylamino)(phenyl)methylphos-
The objective of this paper is to evaluate the utility of a popular phonates (Scheme 1) with good yields (59–86%). Unfortu-
three component reaction of triaryl phosphites with aldehydes nately, the reaction of phosphite obtained from 7-hydroxy-
and benzyl carbamates (the so called Oleksyszyn reaction) for coumarine failed, since it appeared to be unstable upon harsh
the synthesis of fluorescent (benzyloxycarbonylamino)- reaction conditions and underwent decomposition as seen by
(aryl)methylphosphonates.
31P NMR. Therefore, we have decided to apply a more delicate
procedure described recently by Goldeman and Soroka [21].
According to this procedure the reaction was carried out in dry
chloroform in the presence of catalytic amounts of tetrafluoro-
boric acid. Unfortunately, tri(7-hydroxycoumaric) phosphite
also underwent decomposition under these conditions.
Results and Discussion
Synthesis of diaryl (benzyloxycarbonyl-
amino)(phenyl)methylphosphonates
Diaryl esters of Z-protected aminobenzylphosphonic acid were
obtained by using the classical three-component amidoalkyla-
tion procedure described by Oleksyszyn et al. (Scheme 1) [14].
The diaryl esters 2 exhibit restricted rotation around the C–N
bound of their carbamate group. As a consequence, they exist in
First, appropriate triaryl phosphites have to be synthesized. solution in cis- and trans-forms, with the equilibrium strongly
They were obtained by refluxing stoichiometric quantities of shifted towards the formation of trans-isomers [22].
phosphorus trichloride with the appropriate phenol (molar ratio
Synthesis of diaryl (benzyloxycarbonyl-
1:3) in acetonitrile [16,17]. The desired phosphites deposited
from acetonitrile as solids or oils and did not require further amino)(aryl)methylphosphonates
purification. Corresponding reactions carried out in different By applying the same procedure we have synthesized a small
solvents (toluene, benzene or diethyl ether in the presence of library of diaryl esters of aromatic Z-aminophosphonates
butyllithium in hexane) or with phosphorus tribromides gave far (Scheme 2). They were obtained in satisfactory yields
Scheme 1: Diaryl (benzyloxycarbonylamino)(phenyl)methylphosphonates.
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Beilstein J. Org. Chem. 2014, 10, 741–745.
Scheme 2: Diaryl (benzyloxycarbonylamino)(aryl)methylphosphonates.
(55–84%). When using 5-anthracenylaldehyde a complex mix- into the monoester by hydrolysis with aqueous potassium
ture of products was obtained and the product was isolated by hydroxide in the presence of 18-crown-6 [25,26]. The obtained
column chromatography in a low yield of 1% as the mono- monoester 4 was transformed into chloride 5 or bromide 6,
phenyl ester.
which were used in the next step of the synthesis without purifi-
cation (Scheme 4). Upon halogen introduction a new chirality
This library was enlarged by application of the Suzuki–Miyaura center is formed at the phosphorus atom and the products 5 and
approach with compounds 2e and 2k being chosen as substrates 6 were obtained as unequimolar mixtures of diastereoisomers
(Scheme 3) [23,24]. Despite the enormous number of data (45:55 and 42:58 respectively). Upon reaction with an excess of
considering application of this reaction, according to the best of aliphatic alcohol mixed esters of reversed configuration were
our knowledge, there is no report on its application to synthe- obtained, as indicated by the reversed order of the 31P NMR
size phosphorus esters. After dissolving the substrates the cata- peaks. This is in agreement with the mechanism of this reaction,
lyst was added to the reaction mixture and it was carried under which proceeds with inversion of the configuration at the phos-
reflux for 6 h. Optimization of the reaction conditions revealed phorus atom. Upon purification of the obtained compounds 7,
that a mixture of dioxane and water (out of: dioxane, acetoni- either by crystallization or column chromatography, a signifi-
trile, chloroform and acetonitrile/water mixture) appeared to be cant enrichment in one of the diastereomers had been observed.
the best solvent with 5% of Pd(PPh3)4 serving as optimal cata- For example, compound 7b obtained as a 55:45 molar mixture
lyst.
of stereoisomers after purification by means of chromatography
was obtained as 85:15 molar mixture.
Synthesis of mixed esters of (benzyloxycar-
bonylamino)(aryl)methylphosphonates
The approach to obtain mixed esters bearing two aromatic
Also a small library of mixed esters was obtained. Using the moieties is far more difficult as shown by reaction of chloride 5
procedures worked out in our laboratory diphenyl (benzyloxy- with 2-naphthol providing compound 7g. This reaction was
carbonylamino)(phenyl)methylphosphonate (2a) was converted carried out in chloroform in the presence of triethylamine.
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Beilstein J. Org. Chem. 2014, 10, 741–745.
Scheme 3: Diaryl (benzyloxycarbonylamino)(aryl)methylphosphonates obtained by Miyaura–Suzuki approach.
Scheme 4: Synthesis of mixed esters.
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Beilstein J. Org. Chem. 2014, 10, 741–745.
11.Oleksyszyn, J.; Powers, J. C. Biochemistry 1991, 30, 485–493.
doi:10.1021/bi00216a026
Fluorescence
Fluorescence of the representative examples of the obtained
compounds was measured upon irradiation of two wavelengths
of 254 and 366 nm. Compounds 2n and 3g exhibited strong
fluorescence under both conditions. The remaining phospho-
nates either show a weak (2h, 3b, 3d and 3e) fluorescence when
irradiated with 254 nm or exhibited the lack of fluorescence (2f,
2k, 2m, 2o, 3a, 3c, 4, 7a, 7d, 7e, 7g).
12.Sieńczyk, M.; Oleksyszyn, J. Curr. Med. Chem. 2009, 16, 1673–1687.
doi:10.2174/092986709788186246
13.Mucha, A.; Kafarski, P.; Berlicki, Ł. J. Med. Chem. 2011, 54,
5955–5980. doi:10.1021/jm200587f
14.Olekszyszyn, J.; Subotkowska, L.; Mastalerz, P. Synthesis 1979,
985–986. doi:10.1055/s-1979-28903
15.Birner-Gruenberger, R.; Hertmetter, A.; Riesenhuber, G.;
Schmidinger, H.; Suzani-Etzerod, H. Fluorescent phosphonic ester
library. WO Patent WO2006010403 A1, Feb 6, 2006.
16.Walsh, E. N. J. Am. Chem. Soc. 1959, 81, 3023–3026.
doi:10.1021/ja01521a028
Supporting Information
17.Soroka, M. Liebigs Ann. Chem. 1990, 331–334.
doi:10.1002/jlac.199019900162
Supporting Information File 1
Experimental procedures and analytical data and NMR
spectra.
18.Winiarski, L.; Oleksyszyn, J.; Sieńczyk, M. J. Med. Chem. 2012, 55,
6541–6553. doi:10.1021/jm300599x
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-68-S1.pdf]
19.Burchacka, E.; Walczak, M.; Sieńczyk, M.; Dubin, G.; Zdżalik, M.;
Potempa, J.; Oleksyszyn, J. Bioorg. Med. Chem. Lett. 2012, 22,
5574–5578. doi:10.1016/j.bmcl.2012.07.011
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Acknowledgements
Support from both the National Science Centre, Poland
(National Science Centre grant no. N N403 154640 "Design of
peptide libraries and metabolomics studies as a tool in the diag-
nosis of thyroid cancer") and Wroclaw Research Centre EIT+
under the project ‘‘Biotechnologies and advanced medical tech-
nologies’’– BioMed (POIG.01.01.02-02-003/08) is gratefully
acknowledged.
21.Goldeman, W.; Soroka, M. Synthesis 2010, 2437–2445.
doi:10.1055/s-0029-1218817
22.Rudzińska, E.; Berlicki, Ł.; Kafarski, P.; Lämmerhofer, M.; Mucha, A.
Tetrahedron: Asymmetry 2009, 20, 2709–2714.
doi:10.1016/j.tetasy.2009.11.003
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