A Selective Deprotection Strategy for the Construction of trans-2-Aminocyclopropanecarboxylic Acid Derived Peptides

Article abstract of DOI:10.1021/acs.orglett.8b03533

A procedure allowing access to unprecedented tripeptides containing a trans-2-aminocyclopropanecarboxylic acid residue in their central position has been established. The key features of the strategy are the use of a masked trans-2-aminocyclopropanecarbox

Full text of DOI:10.1021/acs.orglett.8b03533

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
A Selective Deprotection Strategy for the Construction of trans-2-
Aminocyclopropanecarboxylic Acid Derived Peptides
Thomas Boddaert,† James E. Taylor,
†,‡
Steven D. Bull,* and David J. Aitken*
,‡
,†
†
ICMMO, CNRS, Universite
́
Paris-Sud, Universite
Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, U.K.
S Supporting Information
́
Paris-Saclay, 15 rue Georges Clemenceau, 91405 Orsay Cedex, France
‡
*
ABSTRACT: A procedure allowing access to unprecedented tripeptides containing a trans-2-aminocyclopropanecarboxylic
acid residue in their central position has been established. The key features of the strategy are the use of a masked trans-2-
aminocyclopropanecarboxylic acid monomer equivalent for C-terminal coupling and full N-Boc protection of all amide groups
until the final step.
arbocyclic β-amino acids are an important molecular
withdrawing group that serves to suppress the deleterious ring
opening reaction.
C
class whose structures appear in natural products and
1
pharmacologically active molecules. They have also been used
ubiquitously as building blocks for the construction of peptidic
2
foldamers. Consequently, various methodologies have been
3
established for the selective synthesis of such compounds.
Within this family, 2-aminocyclopropanecarboxylic acid
(
ACPrC) represents a special case: the free amino acid has
never been described because its high ring strain coupled with
the vicinal donor−acceptor substituent profile induces rapid
and irreversible ring opening, in a retro-Mannich type reaction
4
(Figure 1).
Figure 2. Previously described nonracemic ACPrC derivatives and the
derivatives used in this work.
Figure 1. ACPrC core structure and its inherent ring opening
reactivity.
Given these stability problems, peptides incorporating
ACPrC residues are extremely rare. Reiser found that an
extra carboxylate group at the cyclopropane 3-position
stabilized the cACPrC core sufficiently to facilitate the
preparation of short peptides, some of which displayed
The preparation of ACPrC derivatives is therefore a
considerable challenge, for which a number of approaches
5
,6
have been investigated. Syntheses of protected derivatives of
the trans isomer (tACPrC) have been achieved via
desymmetrization of trans-cyclopropane-1,2-dicarboxylates fol-
12
13
biological activity, organocatalytic activity, and foldamer
14
propensity. These reports demonstrate the considerable
potential of ACPrC peptides; however, procedures for the
preparation of peptides containing unsubstituted ACPrC
residues are severely limited. North was able to desymmetrize
cis-cyclopropane-1,2-dicarboxylic anhydride using proline
followed by a Curtius rearrangement, to afford a urea-based
7
lowed by Curtius rearrangement, ring closure of β-amino-γ-
8
iodobutyrates, substitution of β-bromocyclopropane-
9
carboxamides, or asymmetric cyclopropanation of vinylamide
1
0
derivatives. Approaches to the synthesis of protected
derivatives of the cis isomer (cACPrC) are more limit-
7
c,10b,11
ed.
Stable ACPrC derivatives which have been prepared
to date are presented in Figure 2. It is significant that in all
Received: November 5, 2018
these compounds, the amine invariably bears an electron-
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03533
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
pseudopeptide incorporating cACPrC, as well as a carbamate
Scheme 1. Coupling of tACPrC 1 at the C-terminal
t
protected dipeptide, Teoc-cACPrC-Pro-OBu . However, efforts
15
to deprotect the latter resulted in complete degradation.
Mangelinckx and De Kimpe used the N-diphenylmethylidene
DPM) derivative of tACPrC to prepare the dipeptide DPM-
(
tACPrC-Gly-OMe, but once again reaction of the N-terminus
8
was precluded. Therefore, there is currently no viable
procedure for the construction of peptides which include
16
unsubstituted ACPrC as an internal or C-terminal residue.
We decided to address this deficiency and elaborate a
protocol which would allow access to a tripeptide containing
tACPrC as the internal residue. For this endeavor, the choice
of monomer building blocks was critical: while the doubly
protected derivative 1 appeared a good choice as a C-terminal
coupling partner, none of the tACPrC derivatives in Figure 1
seemed likely to tolerate N-deprotection without ring opening.
For this reason, we selected a masked tACPrC derivative,
compound 2, as a key building block (Figure 2). We envisaged
that Boc removal and then N-coupling should be straightfor-
ward, since there would be no risk of ring opening of the
vicinal benzyloxymethyl substituent. Thereafter, oxidation of
the deprotected primary alcohol would provide the free acid
for C-terminal coupling. Compound 2 was readily available in
17
three steps starting from (S)-glycidol benzyl ether, and it also
served as a convenient precursor for compound 1 using the
18
three-step procedure of Vederas, which involves introduction
of a second Boc group, debenzylation, and oxidation (see
Supporting Information). Protection of the amine as its di-Boc
derivative was essential for the success of the oxidation step,
since degradation occurred when only one Boc group was
present. Catalytically generated ruthenium tetroxide conditions
were chosen for the oxidation step, because these conditions
had been used previously for the successful oxidation of related
19
cyclopropyl alcohols to their corresponding acids.
Our first objective was to prepare dipeptides of general
structure Pg-tACPrC-Xaa-OR. Coupling of 1 with each of four
standard α-amino esters 3a−d was carried out using 1-(3-
(
(
dimethylamino)propyl)-3-ethyl carbodiimide hydrochloride
EDCI·HCl) and 1-hydroxybenzotriazole hydrate (HOBt·
Figure 3. X-ray diffraction structure of compound 4d.
H O) in the presence of triethylamine in dichloromethane
2
for 24 h. The corresponding dipeptides 4a−4d were obtained
in good to excellent yields (73−99%) and proved to be stable
(Scheme 1).
hindrance, respectively. The corresponding derivatives 7a and
7b were obtained in high 86% and 87% yields, respectively
(Scheme 2).
Considering that the transformation of monomer 2 into
monomer 1 required double Boc-protection of the amine, we
took the same precaution during the C-terminal oxidation
steps that were conducted on derivatives 7a and 7b. Use of a
Dipeptide 4d gave crystals which were suitable for X-ray
diffraction analysis (CCDC 1841687, Figure 3). To the best of
our knowledge, solid state structural data for tACPrC
derivatives have not been reported previously. As well as
confirming the (1R,2R) absolute configuration, the crystal
structure revealed a very large dihedral angle (N−Cβ−Cα−
CO) of −138.01°, which was considerably greater than the
corresponding value (around 96°) for trans-cyclobutane-β-
large excess of di-tert-butyl dicarbonate (Boc O) and a catalytic
2
amount of DMAP enabled a second tert-butyl carbamate group
to be introduced onto the nitrogen atoms of 7a and 7b,
providing 8a and 8b in good 73% and 84% yields, respectively
(Scheme 2). Each of these compounds was debenzylated by
hydrogenolysis to give 9a and 9b in near-quantitative yield.
Gratifyingly, oxidation of 9a gave glycyl dipeptide 10a in an
excellent 93% yield. However, oxidation of 9b gave
pyroglutamyl dipeptide 10b as the major product in 65%
yield, along with the anticipated prolyl dipeptide 10c in 17%
yield. Ruthenium tetroxide mediated oxidation of protected
prolyl residues and pyrrolidine systems has been reported
20
amino acid derivatives.
We then turned our attention to the more challenging
preparation of dipeptides of general structure Pg-Xaa-tACPrC-
OH, for which the requisite monomer was compound 2. It was
reasoned that the most convenient way to carry out
deprotection of 2 was to treat it with TFA and use the
resultant ammonium salt directly in coupling reactions.
Therefore, compound 2 was treated with an excess of TFA
in dichloromethane for 2 h, and the resulting salt 5 coupled
(
EDCI·HCl, HOBt·H O, Et N, dichloromethane) with two
2 3
21,22
representative N-Boc-protected α-amino acids 6a and 6b,
previously,
competing formation of the pyrrolidinone ring
which were selected for their low and high degrees of steric
of 10b suggests a limitation of this oxidative methodology. All
B
DOI: 10.1021/acs.orglett.8b03533
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Coupling of Masked tACPrC 5 at the N-Terminal
Scheme 3. Synthesis of Tripeptides 12a and 12b
target compounds were sufficiently stable to be purified by
standard column chromatography on silica gel and could be
stored for several months at −18 °C without any visible
degradation.
In summary, we have demonstrated a viable strategy for the
preparation of di- and tripeptides that contain the elusive β-
amino acid tACPrC as a central unit. While the monomer itself
is inherently unstable, stable peptides can be constructed using
appropriately masked derivatives, with the deprotected residue
being revealed after suitable peptide coupling reactions have
been carried out. This approach should, in principle, be
applicable for the syntheses of other tACPrC derived peptides
of different lengths and composition.
three derivatives 10a−c proved to be stable dipeptides
featuring an unprotected tACPrC at their C-terminals.
The final challenge was to prepare a tripeptide system of the
type Pg-Xaa-tACPrC-Xaa-OR. Both dipeptides 10a and 10b
were activated (EDCI·HCl, HOBt·H O, Et N, dichloro-
2
3
methane) and coupled with tryptophan ethyl ester 3d. The
corresponding tripeptides 11a and 11b were obtained in good
8
6% and 84% yields, respectively (Scheme 3). The final
deprotection step was crucial, requiring removal of the internal
Boc group to reveal an amide bond, while maintaining the
terminal amine N-Boc group to avoid the unwanted ring
opening process. We chose not to use a Brønsted acid (TFA,
or HCl(aq)) because these conditions would be likely to induce
full deprotection of all the N-Boc groups of 11a. Consequently,
we sought to identify a suitable Lewis acid that would enable
selective deprotection. Treatment of 11a with lithium bromide
in acetonitrile was ineffective at room temperature and induced
rapid degradation upon heating. However, prompted by the
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03533.
Experimental procedures, spectroscopic data, and copies
1
13
of H and C NMR spectra for all new compounds
PDF)
23
methodology developed by Martin, we found that treatment
of 11a with magnesium perchlorate in dichloromethane at
room temperature allowed selective cleavage of two out of the
three N-Boc groups, affording the N- and C-terminal protected
tripeptide 12a in 71% yield. These conditions were then
applied to compound 11b, providing access to the globally
deprotected tripeptide 12b in 72% yield (Scheme 3). These
(
Accession Codes
CCDC 1841687 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-
C
DOI: 10.1021/acs.orglett.8b03533
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(11) Herle,
, 3668−3675.
12) (a) Urman, S.; Gaus, K.; Yang, Y.; Strijowski, U.; Sewald, N.;
De Pol, S.; Reiser, O. Angew. Chem., Int. Ed. 2007, 46, 3976−3978.
b) Lang, M.; Bufe, B.; De Pol, S.; Reiser, O.; Meyerhof, W.; Beck-
́
B.; Holstein, P. M.; Echavarren, A. M. ACS Catal. 2017,
7
(
AUTHOR INFORMATION
Corresponding Authors
■
(
Sickinger, A. G. J. Pept. Sci. 2006, 12, 258−266. (c) Koglin, N.; Zorn,
C.; Beumer, R.; Cabrele, C.; Bubert, C.; Sewald, N.; Reiser, O.; Beck-
Sickinger, A. G. Angew. Chem., Int. Ed. 2003, 42, 202−205.
*
E-mail: david.aitken@u-psud.fr.
E-mail: s.d.bull@bath.ac.uk.
*
(
3
13) D’Elia, V.; Zwicknagl, H.; Reiser, O. J. Org. Chem. 2008, 73,
ORCID
262−3265.
Thomas Boddaert: 0000-0002-3939-4700
James E. Taylor: 0000-0002-0254-5536
Steven D. Bull: 0000-0001-8244-5123
David J. Aitken: 0000-0002-5164-6042
Notes
(14) De Pol, S.; Zorn, C.; Klein, C. D.; Zerbe, O.; Reiser, O. Angew.
Chem., Int. Ed. 2004, 43, 511−514.
(
15) Hibbs, D. E.; Hursthouse, M. B.; Jones, I. G.; Jones, W.; Malik,
K. M. A.; North, M. Tetrahedron 1997, 53, 17417−17424.
16) In an isolated case, desilylation of (TMS) -(3-methyl-ACPrC)-
(
2
OMe in the presence of Ts-Phe-Cl was carried out to afford dipeptide
Ts-Phe-(3-methyl-ACPrC)-OMe as a mixture of stereoisomers.
However, this procedure is unlikely to be generally applicable for
the synthesis of ACPrC derivatives. See: Paulini, K.; Reissig, H.-U.
Liebigs Ann. Chem. 1994, 1994, 549−554.
(17) Armstrong, A.; Scutt, J. N. Org. Lett. 2003, 5, 2331−2334.
(18) Jain, R. P.; Vederas, J. C. Org. Lett. 2003, 5, 4669−4672.
(19) (a) Godier-Marc, E.; Aitken, D. J.; Husson, H.-P. Tetrahedron
Lett. 1997, 38, 4065−4068. (b) Roy, O.; Faure, S.; Aitken, D. J.
Tetrahedron Lett. 2006, 47, 5981−5984.
20) (a) Fernandes, C.; Faure, S.; Pereira, E.; Ther
V.; Guillot, R.; Aitken, D. J. Org. Lett. 2010, 12, 3606−3609.
b) Altmayer-Henzien, A.; Declerck, V.; Farjon, J.; Merlet, D.; Guillot,
R.; Aitken, D. J. Angew. Chem., Int. Ed. 2015, 54, 10807−10810.
21) For a previous report where ruthenium catalyzed oxidation
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank COST (Action CM0803) for a Short
Term Scientific Mission grant to J.E.T. We are grateful to R.
Guillot (Services Communs, ICMMO) for the X-ray
diffraction analysis.
(
́
y, V.; Declerck,
REFERENCES
1) (a) Kiss, L.; Forro,
Proteins in Organic Chemistry; Hughes, A. B., Ed.; Wiley: Weinheim,
■
(
́
E.; Fu
̈
lo
̈
p, F. In Amino Acids, Peptides and
(
2
009; Vol. 1, pp 367−409. (b) Juaristi, E., Soloshonok, V., Eds.,
(
Enantioselective Synthesis of β-Amino Acids, 2nd ed.; Wiley: Hoboken,
NJ, 2005. (c) Cabrele, C.; Martinek, T. A.; Reiser, O.; Berlicki, Ł. J.
Med. Chem. 2014, 57, 9718−9739.
resulted in formation of pyroglutamic derivatives, see: Yoshifuji, S.;
Tanaka, K.-I.; Kawai, T.; Nitta, Y. Chem. Pharm. Bull. 1986, 34,
3
(
873−3878.
22) For a recent example, see: Jin, S.; Gong, J.; Qin, Y. Angew.
Chem., Int. Ed. 2015, 54, 2228−2231.
23) Hernandez, J. N.; Ramírez, M. A.; Martín, V. S. J. Org. Chem.
003, 68, 743−746.
(
2) (a) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev.
2
2
2
001, 101, 3219−3232. (b) Guichard, G.; Huc, I. Chem. Commun.
011, 47, 5933−5941. (c) Martinek, T. A.; Fulop, F. Chem. Soc. Rev.
012, 41, 687−702.
3) (a) Kiss, L.; Fu
b) Fulop, F. Chem. Rev. 2001, 101, 2181−2204.
4) (a) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151−
̈
̈
(
2
́
(
̈
lop, F. Chem. Rev. 2014, 114, 1116−1169.
̈
(
̈
̈
(
1
196. (b) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321−347.
(
5) Gnad, F.; Reiser, O. Chem. Rev. 2003, 103, 1603−1623.
6) For selective syntheses of more highly substituted compounds
(
that contain ACPrC cores (including formal examples), see:
(
1
a) Manabe, A.; Matsumoto, R.; Shinada, T. Synlett 2015, 26,
710−1714. (b) Bolm, C.; Schiffers, I.; Atodiresei, I.; Hackenberger,
C. P. R. Tetrahedron: Asymmetry 2003, 14, 3455−3467. (c) Su, J.;
Qiu, G.; Liang, S.; Hu, X. Synth. Commun. 2005, 35, 1427−1433.
(
(
1
d) Lu, T.; Song, Z.; Hsung, R. P. Org. Lett. 2008, 10, 541−544.
e) de Nanteuil, F.; Waser, J. Angew. Chem., Int. Ed. 2011, 50, 12075−
2079. (f) Keita, M.; De Bona, R.; Dos Santos, M.; Lequin, O.;
Ongeri, S.; Milcent, T.; Crousse, B. Tetrahedron 2013, 69, 3308−
3
315. (g) Gu, P.; Su, Y.; Wu, X. P.; Sun, J.; Liu, W.; Xue, P.; Li, R.
Org. Lett. 2012, 14, 2246−2249. (h) Xie, M.-S.; Zhou, P.; Niu, H.-Y.;
Qu, G.-R.; Guo, H.-M. Org. Lett. 2016, 18, 4344−4347.
(
7) (a) Hugentobler, K. G.; Rebolledo, F. Org. Biomol. Chem. 2014,
1
2, 615−623. (b) Miller, J. A.; Hennessy, E. J.; Marshall, W. J.;
Scialdone, M. A.; Nguyen, S. T. J. Org. Chem. 2003, 68, 7884−7886.
c) Martín-Vila, M.; Muray, E.; Aguado, G. P.; Alvarez-Larena, A.;
Branchadell, V.; Minguillon, C.; Giralt, E.; Ortuno, R. M. Tetrahedron:
Asymmetry 2000, 11, 3569−3584.
8) Meiresonne, T.; Mangelinckx, S.; De Kimpe, N. Tetrahedron
012, 68, 9566−9571.
9) Banning, J. E.; Gentillon, J.; Ryabchuk, P. G.; Prosser, A. R.;
(
̀
́
̃
(
2
(
Rogers, A.; Edwards, A.; Holtzen, A.; Babkov, I. A.; Rubina, M.;
Rubin, M. J. Org. Chem. 2013, 78, 7601−7616.
(
10) (a) Chanthamath, S.; Nguyen, D. T.; Shibatomi, K.; Iwasa, S.
Org. Lett. 2013, 15, 772−775. (b) Brandenberg, O. F.; Prier, C. K.;
Chen, K.; Knight, A. M.; Wu, Z.; Arnold, F. H. ACS Catal. 2018, 8,
2
629−2634.
D
DOI: 10.1021/acs.orglett.8b03533
Org. Lett. XXXX, XXX, XXX−XXX