1,3-Оксазоли як попередники фосфорильованих амінокислот і пептидоміметиків
The design and development of new phosphorus-containing amino acids and peptidomimetics have been attracting considerable attention due to their value as intermediates in the synthesis of biologically active compounds and the prospects for further pharmacological applications. 1,3-Oxazole derivative...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2022
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Ukrainica Bioorganica Acta| _version_ | 1871193543278592000 |
|---|---|
| author | Brusnakov, Mykhailo Y. Golovchenko, Oleksandr V. Potikha, Lyudmyla M. Brovarets, Volodymyr S. |
| author_facet | Brusnakov, Mykhailo Y. Golovchenko, Oleksandr V. Potikha, Lyudmyla M. Brovarets, Volodymyr S. |
| author_institution_txt_mv | [
{
"author": "Mykhailo Y. Brusnakov",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Oleksandr V. Golovchenko",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Lyudmyla M. Potikha",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Volodymyr S. Brovarets",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
}
] |
| author_sort | Brusnakov, Mykhailo Y. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:52Z |
| description | The design and development of new phosphorus-containing amino acids and peptidomimetics have been attracting considerable attention due to their value as intermediates in the synthesis of biologically active compounds and the prospects for further pharmacological applications. 1,3-Oxazole derivatives, as masked peptides, constitute an important group of amino acid precursors that are widely used in contemporary organic synthesis. This review presents the 1,3-oxazole-based synthetic strategies of phosphorylated amino acids and peptides that have been published in both journal and patent literature. We have focused specifically on the synthesis of 4-phosphorylated 1,3-oxazoles as precursors of phosphopeptide mimetics containing the peptide chain with a non-terminal phosphono group due to the growing interest in finding efficient methods for the synthesis of this little-studied class of compounds. |
| doi_str_mv | 10.15407/bioorganica2022.01.072 |
| first_indexed | 2025-07-17T12:19:24Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
UDC 577.1:547.94
DOI: https://doi.org/10.15407/bioorganica2022.01.072
72
Ukrainica Bioorganica Acta
www.bi oorgan ica .org .ua
DIGEST PAPER
1,3-Oxazoles as precursors of phosphorylated amino acids
and peptidomimetics
Mykhailo Y. Brusnakov, Oleksandr V. Golovchenko, Lyudmyla M. Potikha, Volodymyr S. Brovarets*
V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine
Abstract: The design and development of new phosphorus-containing amino acids and peptidomimetics have been attracting considerable
attention due to their value as intermediates in the synthesis of biologically active compounds and the prospects for further
pharmacological applications. 1,3-Oxazole derivatives, as masked peptides, constitute an important group of amino acid precursors that are
widely used in contemporary organic synthesis. This review presents the 1,3-oxazole-based synthetic strategies of phosphorylated amino
acids and peptides that have been published in both journal and patent literature. We have focused specifically on the synthesis of
4-phosphorylated 1,3-oxazoles as precursors of phosphopeptide mimetics containing the peptide chain with a non-terminal phosphono
group due to the growing interest in finding efficient methods for the synthesis of this little-studied class of compounds.
Keywords: phosphorylated amino acids; peptidomimetics; phosphorylated 1,3-oxazoles; synthesis.
Introduction
Structural analogues of peptides in which the
aminocarboxylic acid group is replaced by the
aminophosphonic acid group are well known today [1, 2]. A
significant contribution to the development of chemistry of
phosphonopeptidomimetics was made by V. P. Kukhar and
a group of scientists from the Institute of Bioorganic
Chemistry and Petrochemistry of the National Academy of
Sciences of Ukraine under his leadership. In particular,
methods of synthesis were developed and the properties of a
wide range of peptidomimetics, including those containing
a phosphonate group, were studied. A significant amount of
research has also been done in the field of chemistry of
aminophosphonic acids and aminophosphonates as
bioisosteric analogues of natural amino acids. The growing
interest in this class of compounds is due to the fact
Received:
Revised:
Accepted:
Published online:
23.03.2022
08.04.2022
27.04.2022
30.06.2022
Corresponding author. Tel.: +380-44-573-2596;
e-mail: brovarets@bpci.kiev.ua (V. S. Brovarets)
ORCID: 0000-0001-6668-3412
that they have been found in biological systems [3] and are
known to efficiently inhibit enzymes [4-6]. Phosphopeptide
mimetic molecules can be structurally divided into two
types: one containing the peptide chain with a terminal
phosphono group (structures of type A, Figure 1) and the
other with a nonterminal phosphorylated amino acid residue
(structures of type B). The latter type has been much less
studied, since phosphoamino acid group is difficult to
introduce at certain internal positions of polypeptides.
Peptidomimetics of this kind were applied to the synthesis
of natural peptide compounds [7-13], thus adding to the
biological significance of phosphopeptide mimetics.
Reactions for obtaining type A peptides are described in
the review of P. Kafarsky and B. Lejczak [14] as well as in
the later publications [3, 15-17]. V. Brovarets, et al. [18] in
2019 made an attempt to systematize all-data on the
synthetic methods and summarized properties of
petidomimetics of type B. The general strategy of peptide
synthesis of phosphorylated peptidomimetics, as well as
classical peptides, involves the protection of functional
groups with the subsequent formation of a peptide bond.
The final stage of selective removal of protection is usually
the most difficult. In this sense, synthetic schemes based on
the use of P-substituted 1,3-oxazoles as masked amino acids
have certain advantages due to the relative availability of
such compounds and the ability to vary their structure in a
fairly wide range.
© Brusnakov M. Y. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
mailto:brovarets@bpci.kiev.ua
https://orcid.org/0000-0001-6167-076X
Brusnakov M. Y. et al.
73
Figure 1. Structural types of phosphonopeptidomimetics.
In this brief review, we present a selection of literature
data published in the last years, concerning the synthesis of
phosphorylated peptidomimetics of type B, as well as
phosphorylated amino acids as precursors in the synthesis
of such compounds, a method that includes, as a main step,
oxazole ring cleavage.
Synthesis on the base of aromatic 1,3-oxazoles
The first example of the synthesis of phosphorylated
amino acids using 1,3-oxazole derivatives was published by
J. Rachon and U. Schollkopf [19] in 1981. Long-term
storage of oxazoles 1 in methanol or ethanol with HCl
yielded 2-(diethoxyphosphoryl)glycine esters 2 (Scheme 1).
The use of HBr in AcOH gave 2-phosphonoglycine 3 after
48 hours. Reducing the reaction time to 3 min. yields a
mixed esters 4. As expected, the oxazole is hydrolyzed first,
followed by one of the two groups of the phosphonic acid
ester.
Scheme 1. Synthesis of phosphonoglycine derivatives from
5-alkoxy-1,3-oxazoles.
Further, such a scheme was successfully implemented in
the case of 5-amino-1,3-oxazole derivatives 5 [20] (Scheme
2). By solvolysis in 2 N ethanolic HCl were obtained the
phosphonoglycine amide hydrochlorides 6. In contrast to
the ring opening in EtOH, the cleavage in dilute aqueous
HCl yielded amines 7, still formylated on amino group. The
ring opening of an immonium salt 8 took place under very
mild conditions: treatment with aqueous sodium hydrogen
carbonate solution. The direct hydrolysis of the oxazoles 5
under the same weakly basic conditions was not observed.
Scheme 2. Synthesis of phosphonoglycine derivatives from
5-amino-1,3-oxazoles.
It should be noted that the most convenient and popular
approach to a synthesis of 4-phosphorylated derivatives of
5-amino1,3-oxazoles is amination of 1-acyl(formyl)-2,2,2-
trichloroethanephosphonates. The use of 2-substituted
oxazoles allows obtaining the corresponding N-acyl
derivatives of the target amino acids. Thus,
4-phosphorylated oxazoles 9 with isonipecotinic acid
residues at position 5 were easily decomposed by the
heating in an aqueous acetic acid to form the
phosphorylated pseudopeptides 10 [21] (Scheme 3). Owing
to the stability of the oxazol ring in an alkaline medium, the
stepwise hydrolysis of the ester and diethoxyphosphoryl
groups was carried out under the action of sodium
hydroxide. Transformation of compounds 11 in to
pseudopeptides 12 required longer treatment with acetic
acid.
In order to obtain phosphonopeptidomimetics that are
containe acyclic amino alcohol group, oxazoles 13 cleavage
with trifluoroacetic acid was used. In this case, depending
on the temperature of the reaction, it is possible to obtain
esters 14a or acids 14b [22, 23] (Scheme 4).
Scheme 3. Synthesis of phosphorylated pseudopeptides with
isonipecotinic acid residues 10, 12.
The synthesis of peptidomimetics with terminal
haloalkyl and thiocyanoalkyl substituents 15-17 was based
on the interaction of compounds 13 with HCl, HI and
HSCN, respectively, in anhydrous medium [24, 25].
Scheme 4. Synthesis and properties of phosphonopeptidomimetics
containing acyclic amino alcohol groups.
The hydrolytic decomposition of easily available
phthalimido derivatives of 5-alkylamino-2-aminoalkyl-1,3-
oxazol-4-ylphosphonic acids 18a-f in an acidic environment
was performed on heating compounds 18 in 70% aqueous
acetic acid, to form phthalimide-protected phospho-
peptidemimetics 19 in high yields and without laborious
purification [26] (Scheme 5).
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74
Scheme 5. Synthesis phosphopeptidemimetics 19 from
5-alkylamino-2-aminoalkyl-1,3-oxazoles.
The diethyl 5-amino-1,3-oxazol-4-ylphosphonates
substituted at position 2 with aminoalkyl chain 20a, 23 have
been used in the preparation of optically active
phosphorylated peptidomimetics 22, 25 in which the
introduced amino acid residues are not racemized [27].
Acylation of oxazole 20a with Z-(S)-Ala-OH under
standard conditions of peptide synthesis, i.e. in a THF
solution in the presence of 1-hydroxybenzotriazole (HOBt)
and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
(EDCI), also leads only to amide (S)-21 (Scheme 6).
Further oxazole ring opening in (S)-21 was carried out
under mild conditions (in an AcOH-H2O mixture at 75 °C).
Scheme 6. Preparation of optically active phosphorylated
peptidomimetics 22, 25.
A phosphorylated peptidomimetic of more complex
structure 25 was obtained according to a similar scheme.
Oxazole 23 was reacted with Z-protected optically active
(S)-glutamine to give amide (S)-24 (Scheme 6) which
yielded, on ring opening, peptidomimetic (S,R),(S,S)-25
containing the residues of four amino acids ((S)-glutamine,
glycine, phosphorylated glycine, and isonipecotic acid)
[27].
Scheme 7. Synthesis of phosphonodipeptides 28, 29, and 30.
5-Amino-1,3-oxazol-4-ylphosphonic acid derivatives 26,
27 containing a chiral aminoalkyl substituent on the
2-position of the oxazole ring have been used to obtain
phosphonodipeptides 28, 29, and 30 with the original
optical purity retained [28] (Scheme 7). Thus, oxazoles 26,
when heated to 70 °С in 70% aqueous acetic acid, are
cleaved to dipeptides 28 in 90-93% yields, with the
phthaloyl protection of amino groups retained.
Contrastingly, the action of acetic acid on oxazoles 27 leads
to a mixture of unidentified products. To avoid later
pathway the oxazole ring cleavage in these compounds was
performed under milder conditions by using p-toluene-
sulfonic acid in aqueous tetrahydrofuran at 20-25 °С. The
resulting mimetics of phosphornopeptides 29 were isolated
in 90-92% yields.
A combined azlactone/oxazole strategy of the peptide
synthesis was used to synthesize of phosphorylated
peptidomimetics with dehydroamino acid residues [26]. On
heating oxazoles 32 or 33, derived from 5-amino-2-
aminoalkyl-1,3-oxazoles 20a,b, 31a-c, the oxazole ring
opens in 70% aqueous acetic acid to give, in 79-94% yields,
phosphorylated peptidomimetics 34 or 35 (Scheme 8).
Scheme 8. A combined azlactone/oxazole strategy to
peptidomimetics 34-36.
To obtain reduced analogues of compounds 34, authors
attempted, unsuccessfully, direct hydrogenation with zinc in
an AcOH:HCl (10:3) mixture. In contrast, piperidyl
derivatives of oxazoles 32 were thus reduced directly to
peptidomimetics 36 in a good yield (53%-64%).
The azlactone approach makes it possible to purposefully
introduce dehydrtyrozine fragment into phosphorylated
peptidomimetics. Thus, 1,3-oxazole derivatives 39 were
obtained by reacting of 4-phosphorylated derivatives of
5-amino-2-aminoalkyl-1,3-oxazole 20a, 37 with 4-(4-aceto-
xybenzylidene)-2-phenyl-1,3-oxazol-5-one 38 [29] (Scheme
9).
Brusnakov M. Y. et al.
75
Scheme 9. Synthesis of phosphorylated tripeptides with a
dehydrotyrosine fragment 40.
Further compounds 39 were transformed into
phosphorylated tripeptides 40 on heating in a mixture of
acetic acid-water (5 : 1).
In contrast to 4-phosphorylated derivatives of 5-amino-
1,3-oxazole, the corresponding 2,5-diamino derivatives are
more sensitive to both acids and bases, which limits the
availability of such compounds. Only two examples of
4-phosphorylated 2,5-diamino-1,3-oxazoles transformation
to phosphonoglycine amide derivatives have been described
in the literature [30]: treatment of oxazoles 41 with 2 N
aqueous HCl led to the dipeptides 42 (Scheme 10).
Scheme 10. Transformation of 4-phosphorylated 2,5-diamino-1,3-
oxazoles.
The possibility of splitting the 4-phosphorylated
5-mercapto-1,3-oxazoles under the action of acidic reagents
were investigated and led to formation of phosphonoglycine
thioderivatives [31]. In sequential hydrolysis of compounds
43 phosphonoglycine 44 was isolated (Scheme 11).
Scheme 11. Hydrolysis of 5-mercapto-1,3-oxazole 43.
Azlactone approach to the synthesis
Azlactone derivatives are known for their hydrolytic
sensitivity and propensity to open the oxazole cycle under
fairly mild conditions, which is used in the synthesis of
phosphorylated peptidomimetics. Thus, the phosphorus-
containing peptidomimetics 46 were obtained in high yield
under the action of phosphonoglycine amides 45 on 4-(4-
methylbenzylidene)-4,5-dihydro-1,3-oxazol-5-one in
benzene [32] (Scheme 12).
Scheme 12. Synthesis of peptidomimetics 46 from
phosphonoglycine amides.
The high reactivity of azlactones in reactions with both
nucleophilic and electrophilic reagents is used in a number
of synthetic schemes for the construction of phosphorus-
containing derivatives of oxazoles. The introduction of
P-substituent can be carried out in several ways. The key
step is based on Michael reaction.
Scheme 13. Synthesis of -P-aspartic acid derivatives 47 and 48.
For example, β-P-aspartic acid derivatives 47 and 48
were prepared by a one-pot method based on the interaction
of 4-benzylidene-4,5-dihydro-5-oxazolone 49 and alkali
dialkyl phosphites or ClSiMe3, followed by solvolysis with
alcohols or water [33, 34] (Scheme 13). The products 47, 48
are isolated as a mixture of diastereomers with the ratio
depending on the reaction conditions. The key step of
solvolysis is the conversion of intermediate 5-siloxyoxazole
derivatives 50 into hydrolytically unstable azlactons 51.
In the reaction of 4-(phosphonomethyl) 5-siloxyoxazols
50a, 52 with NH-nucleophiles the corresponding amides 53
are formed (Scheme 14). Amines react with compounds 50
only after addition of alcohols. In order to study the
stereochemical features of solvolysis of O-silylderivatives
the method was extended to phenylphosphinates 54 that led
to corresponding P-aspartic acid esters 55 [34] (Scheme
14).
Scheme 14. Synthesis of -P-aspartic acid amides 53 and ethers
55.
Silylphosphanes also gave 1,4-additions with the
O=C-C=C moiety of azlactones to afford the adducts 56
[35]. Oxidation or sulfuration of 56 followed by hydrolysis
led to oxophosphorus (or thiophosphorus) amido-acids 57
and 58 respectively (Scheme 15).
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
76
Scheme 15. Synthesis of oxyphosphorus (or thiophosphorus)
amido-acids 57 and 58.
A difference was observed in the behaviour of
thiophosphane oxides 59a (R = Me) and 59b (R = Ph)
toward hydrolysis: 59a led directly to the amido-acid 58 by
opening of the lactonic ring whereas the heterocyclic
intermediate 60 was isolated from 59b.
Quaternary amino acids containing a geminal
bisphosphonate moiety 61 have been synthesized by a two-
step reaction sequence utilizes the Michael addition of
α-substituted azlactones 62 to a vinylidene bisphosphonate
63 as the key step [36] (Scheme 16).
Scheme 16. Synthesis of amino acid 61 with geminal
bisphosphonate moiety.
The reaction proceeds under catalytic conditions with
excellent regioselectivity. Subsequently, acid-mediated
azlactone ring opening affords the target quaternary amino
acids with good overall yield.
Reaction of azlactones 64 with triphenylvinylphospho-
nium bromide afforded, through a Michael addition, the
azlactones 65 [37] (Scheme 17). Intermediates 65 are
transformed in good yields, without isolation, into the
corresponding -aminoesters 66 or acids 67 functionalized
with a triphenylphosphonium group by reaction with
methanol, ethanol and p-TSA as catalyst or aqueous
hydrogen bromide, respectively.
Scheme 17. Reaction of azlactones with triphenylvinylphospho-
nium bromide.
The phosphonium salts 69 were obtained by
N-acylglycine transformation to 4-phosphoranylidene-
5(4H)-oxazolones 68 and their subsequent alkylation
(Scheme 18).
Scheme 18. Synthesis of N-acyl-α-triphenylphosphonio-α-amino
acid derivatives.
C-Alkylation of 68 with a small alkyl group at position 4
express similar reactivity toward methanol [38, 39] or water
[40, 41] as the protonated ylides. As a result the ring-
opening reaction of oxazolone 70 proceeds, thus leading to
the formation of corresponding N-acyl-α-triphenylphospho-
nio-α-amino acid esters 70a or acid 70b. Acid hydrolysis of
azlactone 68 directly, bypassing the alkylation step, leads to
the amino acid derivatives 71a,b [40, 41].
Phosphorylated sarcosine derivatives 72a and 73 were
obtained by the 1,3-oxazolone ring opening of saturated
azlactones 74 and 75 with benzylamine. When hydrochloric
acid is used, the complete hydrolysis of compound 74 to
acid 72b occurs [42] (Scheme 19).
Scheme 19. Synthesis of phosphorylated sarcosine derivatives.
During efforts to find new approaches to the synthesis of
natural amino acid L-phosphinothricin the hydrolysis of
4-[2-(P)ethyl]-1,3-oxazolidin-5-one derivatives 76a-c as
useful initial building blocks was investigated [43, 44]
(Scheme 20).
Scheme 20. Synthesis of L-phosphinothricin derivatives.
Brusnakov M. Y. et al.
77
The t-butyl per-2-ethylhexanoate-catalyzed reaction of
diisopropylphosphite, dimethylphosphine oxide and
isopropyl methylphosphinate with protected L-vinylglycine
77 afforded the oxazolidinones 76 in moderate yield. The
hydrochlorides 78a,b were obtained as very hygroscopic
crude products by acidic hydrolysis of 76a,b. Treatment of
oxazolidinone 76c with an equimolar amount of NaOH in
THF yielded N-acyl derivative 79, which could be
hydrogenated to 80.
Scheme 21. Synthesis of L-phosphinothricin 82.
A technique involving simple acidic hydrolysis under
heating with decarboxylation of the L-phosphinothricin-N-
carboxylic anhydride 81 was patented for the synthesis of
the optically pure L-phosphinothricin 82 [45] (Scheme 21).
Synthesis based on oxazolidine derivatives
Peptides containing phosphoamino acid
(phosphotyrosine, phosphoserine, phosphotreonine) are
useful tools for understanding signaling. Therefore, there is
considerable interest in (-difluoroalkyl)phosphonates as
analogues of natural phosphates. To construct such
molecules, among others, a multi-stage synthetic scheme
was used, which includes the ring opening cleavage of
phosphorylated oxazolidine derivatives and the oxidation of
intermediate alcohol at the final stage of synthesis. The key
starting reagents are readily available from serine Garner’s
aldehyde 83 and ether 84 (Scheme 22). -P-functionalyzed
4-ethyloxazolidines 85 are obtained in several stages using
as a phosphorylating agent diethyl (difluoromethyl)-
phosphonate. Dowex 50- [46] or HCl-mediated [47] N,O-
acetal cleavage, followed by four-electron Corey-Schmidt
[46] or Ru-catalyzed [47] oxidation of amino alcohols 86
yields the desired Boc-protected analogues of
L-phosphoserine 87a and L-phosphoallothreonine 87b.
Scheme 22. Synthesis of L-phosphoserine and L-phosphoallo-
threonine analogues.
A Horner-Wadsworth-Emmons reaction was performed
on the aldehyde 83 and the resulting phosphonates 88 were
obtained [48-50] (Scheme 23).
Scheme 23. Synthesis of protected derivatives of 2-amino-4-
phosphobutanoic acids 90a-c.
The deprotections of 88 were successively performed in
the presence of dihydrogen and palladium on activated
carbon followed by an acidic treatment in alkanol [48] or
without it in the case of increasing time of hydrogenation
[49]. This two-step procedure gave the alcohol 89a. Then,
the oxidation to the corresponding carboxylic acid 90a was
carried out with a catalytic quantity of TEMPO [48] or
under RuCl3/NaIO4 conditions. The convenient
simultaneous deprotection and oxidation of intermediates
91 with the Jones reagent in acetone led to the protected
aminoacids (R)-90a,b, in one step [49]. A similar sequence
of transformations was patented for the synthesis of
compound 90c [50].
Catalytic hydrogenation of allene 92, which was
obtained in several steps using diethylchlorophosphite, led
to oxazolidine 93. The later was transformed into (2R)-2-
amino-5-phosphonopentanoic acid (AP5) 94 in a similar
sequence of transformations [51] (Scheme 24).
Scheme 24. Synthesis of AP5 94.
Treatment of phosphine sulfide 95 (obtained in several
steps from ester 84 and phosphine) (Scheme 25) with
aqueous acid also had the desired effect of cleaving the
oxazolidine ring. The reaction is followed by
N-deprotection. The best method for oxidation of alcohol 96
was a pyridinium dichromate oxidation in the presence of
molecular sieves, giving the (S)-2-[(tert-butoxycarbo-
nyl)amino]-3-[(diphenylphosphino)sulfide]-1-propanoic
acid 97 in >99% ee [52].
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
78
Scheme 25. Synthesis of 3-[(diphenylphosphino)sulfide]-1-
propanoic acid 97.
An oxazolidinone ring also can be considered as a
synthon for the synthesis of 2-amino alcohols, since it can
be easily cleaved under mild conditions at the two
heteroatoms. Thus, the (α,α-difluoroalkyl)phosphonate
analogue of L-phosphoserine was obtained by base-
mediated oxazolidinone ring cleavage of 98, followed by
the oxidation under the Corey-Schmidt conditions that yield
the desired protected phosphoserine analog 99 [53]
(Scheme 26).
Scheme 26. Synthesis of L-phosphoserine analogue 99.
In the synthesis of phosphonic acid analogue of kainoids,
the same strategy is used to build a synthetic scheme, which
was implemented at the final stage of multistage
transformation [54]. Cleavage of the oxazolidinone ring of
compound 100 was achieved with aqueous base with
subsequent protection of the nitrogen atom with a tert-
butoxycarbonyl group to yield compound 101 (Scheme 27).
Scheme 27. Synthesis of phosphonic acid analogue of kainoids
102.
Oxidation of the primary hydroxy group with
RuCl3/NaIO4 followed, without purification, by
esterification with diazomethane gave fully protected ester
102 in 19.7% yield.
Conclusions
The strategy of constructing synthetic schemes based on
1,3-oxazole derivatives justifies itself both in the case of
synthesis of individual phosphoaminic acids and more
complex peptidomimetics. However, today, the goal of
most work is still to obtain simpler phosphorylated amino
acids. Most of these derivatives were obtained using
popular approaches which includes the hydrolytic ring
cleavage of aromatic oxazoles or azlactones at the final
step. The analysis of literature data presented in this review
indicates the prospects for further development of methods
for modifying the structure of phosphorylated 1,3-oxazoles
as key masked amino acids. Therefore, we hope that this
review will help draw attention to such promising building
blocks for the synthesis of peptides.
Notes
The authors declare no conflict of interest.
Author contributions. The manuscript was written
through the contributions of all authors. All authors have
given approval to the final version of the manuscript.
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ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
80
1,3-Оксазоли як попередники фосфорильованих амінокислот і пептидоміметиків
М. Ю. Бруснаков, О. В. Головченко, Л. М. Потіха, В. С. Броварець*
Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, вул. Мурманська, 1, Київ, 02094, Україна
Резюме: Розробка нових фосфоровмісних амінокислот і пептидоміметиків привертає значну увагу через їх значення як проміжних продуктів у
синтезі деяких біологічно активних речовин та перспективність подальшого фармакологічного застосування. Похідні 1,3-оксазолу, як
замасковані пептиди, становлять важливу групу попередників амінокислот і широко використовуються у сучасному органічному синтезі. У
цьому огляді представлено узагальнення синтетичних стратегій фосфорильованих амінокислот і пептидів на основі 1,3-оксазолу, опублікованих
як у журнальній, так і в патентній літературі. Ми зосередили свою увагу на 4-фосфорильованих 1,3-оксазолах, як попередниках фосфопептидних
міметиків з некінцевою фосфоногрупою в пептидному ланцюгу, у зв’язку із зростаючим інтересом до пошуку ефективних методів синтезу цього
ще малодослідженого класу сполук.
Ключові слова: фосфорильовані амінокислоти; пептидоміметики; фосфорильовані 1,3-оксазоли; синтез.
|
| id | oai:ojs2.bioorganica.com.ua:article-14 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:00:23Z |
| publishDate | 2022 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/ab/23894fc3a012104281346bec04f9b2ab.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-142026-07-19T14:56:52Z 1,3-Oxazoles as precursors of phosphorylated amino acids and peptidomimetics 1,3-Оксазоли як попередники фосфорильованих амінокислот і пептидоміметиків Brusnakov, Mykhailo Y. Golovchenko, Oleksandr V. Potikha, Lyudmyla M. Brovarets, Volodymyr S. phosphorylated amino acids peptidomimetics phosphorylated 1,3-oxazoles synthesis фосфорильовані амінокислоти пептидоміметики фосфорильовані 1,3-оксазоли синтез The design and development of new phosphorus-containing amino acids and peptidomimetics have been attracting considerable attention due to their value as intermediates in the synthesis of biologically active compounds and the prospects for further pharmacological applications. 1,3-Oxazole derivatives, as masked peptides, constitute an important group of amino acid precursors that are widely used in contemporary organic synthesis. This review presents the 1,3-oxazole-based synthetic strategies of phosphorylated amino acids and peptides that have been published in both journal and patent literature. We have focused specifically on the synthesis of 4-phosphorylated 1,3-oxazoles as precursors of phosphopeptide mimetics containing the peptide chain with a non-terminal phosphono group due to the growing interest in finding efficient methods for the synthesis of this little-studied class of compounds. Розробка нових фосфоровмісних амінокислот і пептидоміметиків привертає значну увагу через їх значення як проміжних продуктів у синтезі деяких біологічно активних речовин та перспективність подальшого фармакологічного застосування. Похідні 1,3-оксазолу, як замасковані пептиди, становлять важливу групу попередників амінокислот і широко використовуються у сучасному органічному синтезі. У цьому огляді представлено узагальнення синтетичних стратегій фосфорильованих амінокислот і пептидів на основі 1,3-оксазолу, опублікованих як у журнальній, так і в патентній літературі. Ми зосередили свою увагу на 4-фосфорильованих 1,3-оксазолах, як попередниках фосфопептидних міметиків з некінцевою фосфоногрупою в пептидному ланцюгу, у зв’язку із зростаючим інтересом до пошуку ефективних методів синтезу цього ще малодослідженого класу сполук. V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2022-06-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/14 10.15407/bioorganica2022.01.072 Ukrainica Bioorganica Acta; Vol. 17 No. 1 (2022): Ukrainica Bioorganica Acta; 72-80 Ukrainica Bioorganica Acta; Том 17 № 1 (2022): Ukrainica Bioorganica Acta; 72-80 1814-9766 1814-9758 10.15407/bioorganica2022.01 en https://bioorganica.com.ua/index.php/journal/article/view/14/18 Copyright (c) 2022 Mykhailo Y. Brusnakov, Oleksandr V. Golovchenko, Lyudmyla M. Potikha, Volodymyr S. Brovarets https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | фосфорильовані амінокислоти пептидоміметики фосфорильовані 1,3-оксазоли синтез Brusnakov, Mykhailo Y. Golovchenko, Oleksandr V. Potikha, Lyudmyla M. Brovarets, Volodymyr S. 1,3-Оксазоли як попередники фосфорильованих амінокислот і пептидоміметиків |
| title | 1,3-Оксазоли як попередники фосфорильованих амінокислот і пептидоміметиків |
| title_alt | 1,3-Oxazoles as precursors of phosphorylated amino acids and peptidomimetics |
| title_full | 1,3-Оксазоли як попередники фосфорильованих амінокислот і пептидоміметиків |
| title_fullStr | 1,3-Оксазоли як попередники фосфорильованих амінокислот і пептидоміметиків |
| title_full_unstemmed | 1,3-Оксазоли як попередники фосфорильованих амінокислот і пептидоміметиків |
| title_short | 1,3-Оксазоли як попередники фосфорильованих амінокислот і пептидоміметиків |
| title_sort | 1,3-оксазоли як попередники фосфорильованих амінокислот і пептидоміметиків |
| topic | фосфорильовані амінокислоти пептидоміметики фосфорильовані 1,3-оксазоли синтез |
| topic_facet | phosphorylated amino acids peptidomimetics phosphorylated 1,3-oxazoles synthesis фосфорильовані амінокислоти пептидоміметики фосфорильовані 1,3-оксазоли синтез |
| url | https://bioorganica.com.ua/index.php/journal/article/view/14 |
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