Toward Enantiomerically Pure β-Seleno-α-amino Acids via Stereoselective Se-Michael Additions to Chiral Dehydroalanines

Article abstract of DOI:10.1021/acs.orglett.0c03832

The first totally chemo- and diastereoselective 1,4-conjugate additions of Se-nucleophiles to a chiral bicyclic dehydroalanine (Dha) are described. The methodology is simple and does not require any catalyst, providing exceptional yields at room temperature, and involves the treatment of the corresponding diselenide compound with NaBH4 in the presence of the Dha. These Se-Michael additions provide an excellent channel for the synthesis of enantiomerically pure selenocysteine (Sec) derivatives, which pose high potential for chemical biology applications.

Full text of DOI:10.1021/acs.orglett.0c03832

pubs.acs.org/OrgLett
Letter
Toward Enantiomerically Pure β‑Seleno-α-amino Acids via
Stereoselective Se-Michael Additions to Chiral Dehydroalanines
́
Paula Oroz, Claudio D. Navo, Alberto Avenoza, Jesus H. Busto, Francisco Corzana,
́
́
́
Gonzalo Jimenez-Oses, and Jesus M. Peregrina*
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ABSTRACT: The first totally chemo- and diastereoselective 1,4-
conjugate additions of Se-nucleophiles to a chiral bicyclic
dehydroalanine (Dha) are described. The methodology is simple
and does not require any catalyst, providing exceptional yields at
room temperature, and involves the treatment of the corresponding
diselenide compound with NaBH4 in the presence of the Dha. These
Se-Michael additions provide an excellent channel for the synthesis of
enantiomerically pure selenocysteine (Sec) derivatives, which pose high potential for chemical biology applications.
elenocysteine (Sec, U) is the 21st genetically encoded
amino acid, which is inserted cotranslationally into many
unsaturated carbonyl derivatives with nucleophilic selenium
species affords β-seleno derivatives through Michael-like
addition reactions.10 However, to the best of our knowledge
the asymmetric 1,4-conjugated addition of Se-nucleophiles to
chiral Michael acceptors has not been reported. Hence, and
following the methodology established by our group,11 we
envisioned the synthesis of enantiopure selenoamino acids
using the Se-nucleophilic 1,4-attack to chiral dehydroalanines
as a key step. First, we assayed the 1,4-conjugated addition
using our first generation chiral Dha 1′ as a Michael acceptor
(Scheme 1).11a,b
S
proteins, providing different selenoproteins with a variety of
appreciated redox properties.1,2 Different post-translational
modifications of Sec in selenoproteins have been experimen-
tally validated,2b and selenoamino acids have been used in site-
selective protein modification (SSPM) as precursors of
dehydroalanine (Dha) enabling the introduction of post-
translational modifications or chemical tags in proteins.2
Beyond applications in bioconjugation, selenoamino acids are
particularly relevant in native chemical ligation (NCL), a
versatile chemical approach to prepare large peptides and
proteins that has revolutionized the field of protein science.3
The fundamental improvement of ligation chemistry using
selenoamino acids is that chemoselective deselenization can be
accomplished under mild conditions.4 Moreover, the Sec-
driven NCL is faster, more pH tolerant, and efficient than Cys-
driven NCL,5 allowing the synthesis of selenoproteins in high
yields.6 In addition, some Se-protected Sec, which can be
deprotected and activated on demand, have been genetically
incorporated into proteins.7a,b Several aryl derivatives of Sec
serve as chemical models to understand the inhibition of
selenoenzymes, which has implications for cancer therapy.7c
Thus, synthetic methodologies for generating libraries of
diverse enantiomerically pure selenoamino acids are valuable
to facilitate access to selenopeptides and selenoproteins.7
Selenoamino acids in enantiomerically pure forms are
commonly obtained by nucleophilic substitution reactions. In
this regard, various methods to generate selenated nucleophiles
have been described, especially focusing on the ring-opening
reactions of heterocycles to access a variety of organo-selenium
compounds, including their chiral variants.8,9 Although the Se-
nucleophilic substitution reaction has been deeply explored,
less attention has been paid to 1,4-conjugate addition
reactions. A few examples reported that treatment of α,β-
Scheme 1. Stereoselective Se-Michael Addition to Dha 1′
Phenylselenolate generated in situ from diphenyl diselenide a
in the presence of NaBH4 and acetic acid was used as a
nucleophile in ethanol/dichloromethane (9:1) at room
temperature (Scheme 1). The reaction was fast and
quantitative, although a 70:30 mixture of two diastereoisomers
1
was detected by H NMR (Supporting Information).
Received: November 19, 2020
Published: December 29, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03832
© 2020 American Chemical Society
Org. Lett. 2021, 23, 1955−1959
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This preliminary result was improved using our second
generation chiral Dha (1),11c which showed excellent results in
other Michael-type additions,11d as the Se-Michael acceptor.
Thus, using the same conditions described before, complete
conversion was achieved in 5 min and a single diastereoisomer
2a was obtained (Scheme 2). Other sources of Se-nucleophiles
Scheme 2. Stereoselective Se-Michael Additions of Se-
Nucleophiles to Dha 1 and Synthesis of Selenoamino Acids
Figure 1. ORTEP diagram of compound 2a, showing thermal
ellipsoids at the 75% probability level.
crude reaction mixture, indicating that they occur with
complete diastereoselectivity. This stereochemical outcome
points to a robust stereoinduction mechanism for the
protonation of the enolate adduct formed after conjugate
addition, similar to that previously described for S-Michael
additions11c on Dha 1 (Scheme S3 in Supporting Informa-
tion).
The scope of the reaction of chiral Dha 1 with several Se-
nucleophiles was examined under similar conditions. Other
sources of selenium nucleophile were explored, but the
diselenides in the presence of NaBH4 proved to be more
versatile and facilitated workup. We carried out the conjugate
additions with a wide variety of reagents leading to motifs that
arise in nature via post-translational modifications. In all cases,
high yields and diastereoselectivities were achieved and all the
1,4-conjugate adducts (2a−f) were obtained as single stereo-
isomers (Scheme 2). The absolute configuration of the new
stereocenters was also determined by 2D NOESY-NMR
experiments (Supporting Information), demonstrating that
the same stereochemical outcome was achieved for all Se-
nucleophiles with Dha 1.
L-Phenylselenocysteine (L-PhSec, 3a) is an important amino
acid used in NCL which together with the corresponding
Fmoc-derivative have been prepared by nucleophilic sub-
stitution with Se-nucleophiles on adequately activated Ser-
derivatives.12 The hydrolysis of Se-Michael adduct 2a with
aqueous 4 M HCl at 40 °C yielded enantiomerically pure L-
PhSec 3a in 95% yield (Scheme 2). The stereochemical
integrity of the α-carbon was maintained upon deprotection, as
verified by their optical properties.12 Thus, our methodology
provides an easy entry to N-Fmoc-PhSec12 (Scheme S4 in
Supporting Information) readily available for being used in
solid-phase peptide synthesis.
Se-Michael adduct 2b was easily achieved through 1,4-
conjugate addition of di-p-methoxybenzyl diselenide,
(PMBSe)2, b to Dha 1 in the presence of NaBH4 (Scheme
2). In this case, the acid hydrolysis of the corresponding Se-
Michael adduct 2b gave enantiopure L-selenocystine 4b by
complete hydrolysis of all the protecting groups including
PMB13 and in situ oxidation of the corresponding L-Sec
(Scheme 2 and Scheme 3).
Selenium exerts chemopreventive activity against several
types of cancer.14 Its biologic activity is related to its
incorporation in a diversity of biochemical forms. For instance,
Se-allylselenocysteine (abbreviated as ASC, Seac or Asec, 3c) is
an effective metabolite in inhibiting mammary carcinogenesis,
but its role of cytotoxicity in chemoprevention is unknown.14
In addition, Asec allowed site-specific incorporation of Sec in
proteins.7a Using our methodology, the Se-Michael addition to
Dha 1 was carried out with allylselenocyanate c and NaBH4
were assayed, such as benzeneselenol in the presence of Al2O3
in toluene at room temperature. The conversion was again
quantitative, and the same single diastereoisomer 2a was
obtained (Scheme S2 in Supporting Information).
The absolute configuration of the new stereocenter (C3) of
compound 2a formed in the Se-Michael addition was
determined by X-ray analysis of monocrystals of this
compound (Figure 1). Alternatively, this structural feature
was also determined by a 2D NOESY−NMR experiment on 2a
(Supporting Information).
Remarkably, in the Se-Michael reactions on Dha 1, a single
1
diastereomer was observed in the H NMR spectrum of the
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showed improved antibody recognition properties when
incorporated into a peptide sequence as a result of optimized
peptide/carbohydrate interactions resulting from an O/Se
replacement at the glycosidic linkage. As an entry to
diastereopure Se-Tn mimetics, we assayed the reaction of
diselenosugar f with Dha 1, following the conditions described
in Scheme 2, to give adduct 2f as a single diastereoisomer,
whose stereochemistry was determined by NOE experiments.
Diselenosugar f was prepared from a peracetylated GalNAc
derivative following the methodology previously described by
us.20 Se-Michael adduct 2f was hydrolyzed in an acidic medium
to give Tn antigen mimetic α-D-GalNac-L-Sec 3f (Scheme 2).
In conclusion, this work describes the first totally chemo-
and stereoselective 1,4-conjugate additions of different Se-
nucleophiles to chiral bicyclic dehydroalanine (Dha) 1. The
reactions are carried out using a general, mild, and noncatalytic
methodology and provide good to excellent yields. Se-
nucleophiles are generated in situ from the corresponding
stable and easily accessible or commercially available diselenide
derivatives, by the action of sodium borohydride. Simple acidic
hydrolysis of the corresponding adducts gives access to a small
collection of enantiopure Sec derivatives, such as L-PhSec, L-
selenocystine, L-ASec, L-SeLys, (R,R)- and meso-SeLan, and Tn
antigen mimetic α-Se-GalNAc-L-Sec. In fact, our methodology
comprises a new strategy for the emerging field of stereo-
selective Se-glycosylation.21 In summary, readily available
starting materials, mild conditions, functional group tolerance,
and high yields and stereoselectivities make this strategy an
appealing method for the synthesis of enantiomerically pure
selenoamino acids.
Scheme 3. Synthesis of L-Selenocystine 4b
generating the corresponding adduct 2c with a good yield and
i
stereoselectivity. In this case, PrOH was used as a cosolvent
instead of EtOH to avoid the formation of byproducts arising
from the nucleophilic attack of EtOH to the lactone of Se-
Michael adduct 2c (Scheme S5 in Supporting Information).
This adduct 2c was hydrolyzed to give L-Asec (3c), whose
physical properties match those described in the literature7a,10
(Scheme 2).
Recently, selenium-containing analogues of modified Lys
residues have been developed in order to facilitate traceless
isopeptide bond formation through isopeptide chemical
ligation.15 In addition, it is well-known that 4-selenalysine
(SeLys) has been used as a substitute for Lys to synthesize
artificial lanthipeptides from in vitro translation.16 In general,
the introduction of selenium in the skeleton of amino acid
involves the use of disodium diselenide and tert-butyl (2-
chloroethyl)carbamate to obtain the respective selenium-based
nucleophile di-tert-butyl (diselanediylbis(ethane-2,1-diyl))-
dicarbamate, which is able to react in situ through an SN2
reaction with N-Boc-β-bromoalanine methyl ester giving the
corresponding protected SeLys. As an alternative, we carried
out the stereoselective synthesis of L-SeLys (3d) by Se-Michael
addition of di-tert-butyl (diselanediylbis(ethane-2,1-diyl))-
dicarbamate d to Dha 1 followed by acid hydrolysis (Scheme
2).
Selenolanthionine (SeLan) was selected as another
selenoamino acid target for our methodology. Several reports17
described the synthesis of SeLan, including its incorporation in
lanthipeptides,18 with a renewed interest.19 Optically active
(R,R)-SeLan was synthesized by reacting Dha 1 with the
selenolate derivative of Boc-L-Sec-OMe, which was in situ
generated from Boc-L-selenocystine-OMe e by the action of
NaBH4, to give Se-Michael adduct 2e with a 85% yield and
high diastereoselectivity (Scheme 2). In the same way, the Se-
Michael reaction of e with the enantiomer of Dha 1 (ent-1)
yielded adduct 2′e. (Scheme 4). Both adducts 2e and 2′e were
hydrolyzed to give (R,R)-SeLan 3e (Scheme 2) and meso-
SeLan 3′e in high yields and diastereomeric purities,
respectively (Scheme 4).
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03832.
Experimental procedures, characterization data, and
copies of the NMR spectra (PDF)
Crystallographic data (TXT)
Accession Codes
CCDC 2045571 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Recently, a Se-mimetic of the Tn antigen derived from Thr
[Se-(α-D-GalNac)-L-selenothreonine, abbreviated as α-D-Gal-
Nac-L-SeThr] has been reported.20 Such a Tn antigen mimetic
́
Jesus M. Peregrina − Departamento de Química, Centro de
Investigación en Síntesis Química, Universidad de La Rioja,
26006 Logroño, La Rioja, Spain; orcid.org/0000-0003-
3778-7065; Email: jesusmanuel.peregrina@unirioja.es
Scheme 4. Synthesis of meso-SeLan 3′e
Authors
Paula Oroz − Departamento de Química, Centro de
Investigación en Síntesis Química, Universidad de La Rioja,
26006 Logroño, La Rioja, Spain
Claudio D. Navo − Center for Cooperative Research in
Biosciences (CIC bioGUNE), Basque Research and
Technology Alliance (BRTA), 48160 Derio, Spain;
orcid.org/0000-0003-0161-412X
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expanded genetic code and palladium-mediated chemical depro-
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incorporation of selenocysteine by genetic encoding as a photocaged
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K. M.; Mugesh, G. Modelling the inhibition of selenoproteins by small
molecules using cysteine and selenocysteine derivatives. Chem. - Eur. J.
2019, 25, 8875.
Alberto Avenoza − Departamento de Química, Centro de
Investigación en Síntesis Química, Universidad de La Rioja,
26006 Logroño, La Rioja, Spain
́
Jesus H. Busto − Departamento de Química, Centro de
Investigación en Síntesis Química, Universidad de La Rioja,
26006 Logroño, La Rioja, Spain; orcid.org/0000-0003-
4403-4790
Francisco Corzana − Departamento de Química, Centro de
Investigación en Síntesis Química, Universidad de La Rioja,
26006 Logroño, La Rioja, Spain; orcid.org/0000-0001-
5597-8127
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A.; Braga, R. C. Efficient synthesis of chiral β-seleno amides via ring-
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S.; Davis, B. G. Rapid cross-metathesis for reversible protein
modifications via chemical access to Se-allyl-selenocysteine in
proteins. J. Am. Chem. Soc. 2013, 135, 12156.
́
́
Gonzalo Jimenez-Oses − Center for Cooperative Research in
Biosciences (CIC bioGUNE), Basque Research and
Technology Alliance (BRTA), 48160 Derio, Spain;
orcid.org/0000-0003-0105-4337
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03832
Author Contributions
The manuscript was written through contributions of all
authors./All authors have given approval to the final version of
the manuscript.
Notes
́
́
(11) (a) Aydillo, C.; Avenoza, A.; Busto, J. H.; Jimenez-Oses, G.;
Peregrina, J. M.; Zurbano, M. M. A biomimetic approach to
The authors declare no competing financial interest.
́
lanthionines. Org. Lett. 2012, 14, 334. (b) Aydillo, C.; Companon,
̃
ACKNOWLEDGMENTS
■
I.; Avenoza, A.; Busto, J. H.; Corzana, F.; Peregrina, J. M.; Zurbano,
M. M. S-Michael additions to chiral dehydroalanines as an entry to
glycosylated cysteines and a sulfa-Tn antigen mimic. J. Am. Chem. Soc.
́
We thank the Agencia Estatal Investigacion of Spain (AEI;
Grants RTI2018-099592-B-C21 and RTI2018-099592-B-C22
projects), the Mizutani Foundation for Glycoscience (Grant
200077), and the EU (Marie-Sklodowska Curie ITN,
DIRNANO, Grant Agreement No. 956544). P.O. thanks
Universidad de La Rioja for a grant.
́
́
2014, 136, 789. (c) Gutierrez-Jimenez, M. I.; Aydillo, C.; Navo, C. D.;
́
́
Avenoza, A.; Corzana, F.; Jimenez-Oses, G.; Zurbano, M. M.; Busto, J.
H.; Peregrina, J. M. Bifunctional chiral dehydroalanines for peptide
coupling and stereoselective S-Michael addition. Org. Lett. 2016, 18,
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2796. (d) Navo, C. D.; Mazo, N.; Oroz, P.; Gutierrez-Jimenez, M. I.;
Marín, J.; Asenjo, J.; Avenoza, A.; Busto, J. H.; Corzana, F.; Zurbano,
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