Concise pathway to new multifunctionalized constrained pentacin derivatives by means of two stereospecific tandem reactions

Article abstract of DOI:10.1002/ejoc.201100593

Starting from Boc-activated diketopiperazines, original bicyclic derivatives of trans-and cis-2-aminocyclopentane carboxylic acid were prepared by using two stereospecific tandem reactions. One of them is a tandem transannular rearrangement of activated lactams/alkylation process leading to the stereoselective synthesis of suitably chiral pyrrolidine-2, 4-diones, allowing subsequent Michael-initiated ring closure, a simple and concise route to original multifunctionalized alicyclic ss-amino esters.

Full text of DOI:10.1002/ejoc.201100593

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100593
Concise Pathway to New Multifunctionalized Constrained Pentacin Derivatives
by Means of Two Stereospecific Tandem Reactions
Thibault Coursindel,[a] Jean Martinez,[a] and Isabelle Parrot*[a]
Keywords: Amino acids / Heterocycles / Diastereoselectivity / Ring contraction / Fused-ring systems
Starting from Boc-activated diketopiperazines, original bi-
cyclic derivatives of trans- and cis-2-aminocyclopentane-
carboxylic acid were prepared by using two stereospecific
tandem reactions. One of them is a tandem transannular re-
arrangement of activated lactams/alkylation process leading
to the stereoselective synthesis of suitably chiral pyrrolidine-
2,4-diones, allowing subsequent Michael-initiated ring clo-
sure, a simple and concise route to original multifunction-
alized alicyclic β-amino esters.
be a building block for the preparation of helical foldamers,
whereas homo-oligomers of cis-pentacin form sheet-like
secondary structures in solution.[9]
Introduction
Alicyclic β-amino acids[1,2] are of increasing interest in
the context of drug development, initially due to their intri-
guing potent biological activities and protease-resistant
properties.[3–6] For example, Tilidine is a synthetic opioid
analgesic used for the treatment of moderate to severe pain;
cis-pentacin [(1R,2S)-ACPC, (1R,2S)-2-aminocyclopent-
anecarboxylic acid, Scheme 1],[6] an element of the antibi-
otic amipurimycin, possesses antifungal and antibiotic
properties, whereas its synthetic derivative, iconfungipen
(PLD-118), is a representative of a novel class of strong oral
antifungals.[7] In addition to the research of more-potent
pentacin derivatives, we noticed the emergence of such
backbones in the design of chiral catalysts used in enantio-
selective synthesis,[8] but also a growing interest in the pro-
duction of pentacin oligomer derivatives leading to the de-
velopment of attractive edifices, which could adopt stable
folded conformations. trans-Pentacin [(1S,2S)-ACPC] could
Although numerous substituted derivatives of alicyclic α-
and γ-amino acids have been synthesized and extensively
studied for their biological properties,[10,11] β-derivatives
have been investigated only in a limited number of cases[12]
and mainly for their ability to form original structures.[13–19]
In the cyclopentanic series, a more specific concern has
been dedicated to alkyl derivatives,[20,21] aminated[22] and/or
hydroxylated analogues,[22–27] which is certainly correlated
with the structure of the antibiotic oryzoxymicin.[22] Re-
cently, substituted chiral cyclopentamine derivatives were
synthesized by an original pathway. Their incorporation
into peptide nucleic acids improves binding to RNA and
DNA.[28]
In order to enlarge the molecular diversity of ACPC ana-
logues, for both pharmacological and structural investi-
gations, we report here an original and concise pathway to
access orthogonally protected multifunctionalized cyclo-
pentane β,γ-diamino esters by using two tandem reaction
sequences. Modern design in organic chemistry requires mi-
nimization of the number of steps to construct complex mo-
lecules. Tandem reactions are efficient synthetic approaches
for the construction of relatively complex compounds in a
limited number of steps. In the perspective of stereoselective
synthesis of cyclic β-amino acids synthesis, the MIRC
(Michael-initiated ring closure) reaction, a tandem conju-
gate addition/aldol reaction on ε-oxo-α,β-unsaturated es-
ters, is probably the most extensively applicable. Initiated
by Yamamoto et al.[29–31] and developed by Davies et al.,[25]
nucleophilic addition to α,β-unsaturated esters is followed
by subsequent intramolecular cyclization of the resulting
enolate onto an internal electrophilic entity. Aiming at the
synthesis of rigid pentacin derivatives, we have applied this
relevant reaction to a suitable chiral synthon fashioned
Scheme 1. Examples of bioactive five-membered alicyclic β-amino
acids.
[a] Institut des Biomolécules Max Mousseron (IBMM), UMR
5247 CNRS – Université Montpellier 1 – Université Montpell-
ier 2, cc17-03,
Place Eugène Bataillon, 34095 Montpellier Cedex 5, France
Fax: +33-4-67144866
E-mail: isabelle.parrot@univ-montp2.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100593.
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T. Coursindel, J. Martinez, I. Parrot
SHORT COMMUNICATION
from a regioselective and stereospecific tandem reaction: Thus, we could imagine that the spatial position of the α,β-
the transannular rearrangement of activated lactams unsaturated ester chain, related to the configuration of the
(TRAL)/alkylation (Scheme 2).[32–35]
new stereogenic center fashioned during the TRAL/alk-
ylation, will influence the subsequent intramolecular cycli-
zation.
Scheme 2. Chemical strategy involving two tandem reactions to
access rigid pentacin derivatives, where Nu = –NHR and EWG =
–COOR.
Scheme 3. Reagents and conditions: (a) Boc2O, DMAP, DMF, r.t.,
1.5 h; (b) ethyl 4-bromocrotonate, LiHMDS, THF, –78 °C to r.t.,
overnight; (c) 3% TFA in DCM, 0 °C, 2.5 h; (d) BnNH2, EtOH,
reflux, 4 d.
The alkylating version of TRAL[32] is a useful ring-con-
traction reaction for the stereoselective construction of pyr-
rolidine-2,4-dione motifs from Boc-activated 2,5-diketopip-
erazines (DKPs) as precursors.[35] The challenge of this
work was to combine and potentiate two methodologies,
TRAL/alkylation and MIRC, for the stereoselective synthe-
sis of multifunctionalized alicyclic β-amino esters, ideally
to synthesize derivatives of cis-pentacin or trans-pentacin.
Especially, we focused on the access to novel conformation-
ally restricted structures.
Before applying the MIRC conditions to 3a, a chemose-
lective deprotection of the Boc-protected lactam ring was
essential. Indeed, the carbonyl group of the protected lac-
tam, highly activated by the Boc group, is susceptible to
nucleophilic attack. However, complete N-deprotection of
3a will liberate a nucleophilic amine, in competition with
the nucleophilic entity present during the MIRC reaction.
Without any cleavage of the Boc protecting group of the
primary amine, taking advantage of the difference in reac-
tivity between the two functions, monoprotected heterocy-
Results and Discussion
The synthetic route we developed is based on pioneered cle 4a was obtained in 90% yield.
results on the TRAL/alkylation, allowing the preparation
The most challenging step was the construction of the
of substituted pyrrolidine-2,4-diones from suitably activated pentacin cycle, motivated by the work developed by the
DKPs with total stereoselectivity. Particularly, the N-Boc- group of S. G. Davies.[25] To promote the tandem Michael
activated DKP cyclo-[Gly-(d)-Val] has revealed to be an ap- addition and cyclization reaction, ε-oxo-α,β-unsaturated es-
propriate model to investigate new pathways to original het- ter 4a previously prepared was heated at reflux in ethanol
erocycles.[35] It was then envisaged that insertion of a rel- in the presence of benzylamine. A mixture of isomers 5a_1
evant chain possessing the required properties to be in- and 5a_2 was obtained in an overall yield of 80%, after
volved in a MIRC reaction could allow access to original back recovery of the starting material. Indeed, incomplete
pentacins.
conversion of about 50% of the starting material was ob-
We have previously shown that cyclo-[Gly-(d)-Val] (1a) served, as described by S. G. Davies et al.[25] The starting
after appropriate protection and activation could be suc- product was isolable during the purification by silica gel
cessfully engaged in a TRAL/alkylation reaction. In the chromatography of the crude material, and the reaction was
presence of LiHMDS and ethyl 4-bromocrotonate, 3a can performed one more time to increase the overall efficiency
be prepared in 42% yield in a totally diastereoselective of the process. Intramolecular cyclization onto the cyclic
manner (Scheme 3). Introduction of an α,β-unsaturated es- ketone of the β-amino enol created by benzylamine ad-
ter at this position leading to the creation of a suitable ε- dition allowed the formation of two unprecedented struc-
oxo-α,β-unsaturated ester sequence was crucial at this stage tures. To the best of our knowledge, constrained derivatives
when the goal was to achieve subsequent conjugate ad- of pentacin possessing such quaternary stereocenters have
dition/cyclization (MIRC). This methodology is well docu- not yet been investigated. The bicyclic structures fashioned
mented on acyclic α,β-diunsaturated diesters and also on ε- possess an innovative succession of polyfunctionalities, with
and ζ-formyl-α,β-unsaturated esters,[25] and we thought that an interesting orthogonality in protecting groups, making
the reaction could be extended to cyclic ketones to provide either future incorporation in peptidic sequence or oligo-
access to bicyclic pentacin structures. Instead of homochiral merization feasible. Without any involvement of a chiral
lithium N-benzyl-N-α-methylbenzylamide, our synthetic amine as nucleophilic chiral inducer, using instead a chiral
route involved achiral amines reacting on a chiral unit. platform as a Michael acceptor, a diastereomeric excess of
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Concise Pathway to Multifunctionalized Constrained Pentacin Derivatives
70% was highlighted. The one-step creation of three novel two other chiral centers created on the pentacin isomers
stereogenic centers led only to two different epimers that seems to be guided by the configuration of the chiral center
could be easily separated by simple silica gel chromatog- of the initial (d)-valine present on the starting reagent.
raphy. The stereochemical identity of each pentacin deriva-
This hypothesis could be supported by further studies,
tive was determined and confirmed by 1H NMR spec- where Boc-activated DKP cyclo-[Gly-Val] was used as the
3
troscopy. Particularly, the JH,H coupling constants of the starting material. Following a similar synthetic pathway, we
BnNH-CH-CH-CO2Et moiety in the ring system of the were able to access novel isomers 5b_1 and 5b_2 of amino-
major isomer (14.0 Hz) was much higher than that of the hydroxypentacins with comparable yields and dia-
minor isomer (8.0 Hz). We could establish that the hydroxy stereomeric excess values (Scheme 5). The stereoselectivity
group and the ester moiety of the major isomer were posi- observed was consistent with the above mechanistic predic-
tioned in a trans configuration, similarly to trans-pentacin. tions, allowing us to conclude to a high stereospecificity of
A possible mechanism for the asymmetric MIRC is shown the two tandem reactions involved. Whatever the configura-
in Scheme 4.
tion of the isopropyl moiety present on the starting DKP,
the major product possessed a relative 1,2-trans-1,5-cis con-
figuration, whereas the minor product acquired a relative
1,2-cis-1,5-cis configuration.
Scheme 5. Reagents and conditions: (a) Boc2O, DMAP, DMF, r.t.,
1.5 h; (b) ethyl 4-bromocrotonate, LiHMDS, THF, –78 °C to r.t.,
overnight; (c) 3% TFA in DCM, 0 °C, 2.5 h; (d) BnNH2, EtOH,
reflux, 96 h.
Scheme 4. Proposed model to elucidate the stereospecific tandem
conjugate addition/cyclization reaction.
Conclusions
Inspired by the mechanistic studies described by S. G.
Davies et al.,[25] we could easily assume that the initial step
involved Michael addition of benzylamine to the α,β-unsat-
urated ester, the conjugate addition being concomitant with
the intramolecular addition of the enol onto the cyclic ε-
ketone. However, the mechanism to explain the stereoselec-
tivity observed here is innovative, being specific and totally
dependent of the conformational nature of the scaffold gen-
erated by the TRAL/alkylation. Among the three chiral
centers fashioned in one step, only the one bearing the ben-
zylamine group is not created in a total stereoselective man-
ner. The partial stereoselectivity of its addition can be ex-
plained by preferential addition of the benzylamine on the
less bulky face of 4a, rather than on the space occupied by
the hindered N-Boc group present on the pyrrolidine moi-
ety. Thereafter, the resulting enol has no alternative but to
attack stereoselectively the Si face of the cyclic ketone, forc-
ing the positioning of the carboxy moiety, clustered by the
presence of the isopropyl moiety. To summarize, the config-
uration of the chiral center created by the addition of the
benzylamine is guided by the configuration of the chiral
The tandem TRAL/alkylation combined to the intramo-
lecular tandem conjugate addition/aldol reaction provided
an efficient method for the diastereoselective synthesis of
ethyl 2,4-amino-5-hydroxycyclopentanecarboxylate deriva-
tives. To the best of our knowledge, the polyfunctionaliz-
ation accessible by this synthetic route has no precedent,
leading to the synthesis of highly valuable scaffolds. Further
work will be devoted to their incorporation into novel β-
peptide architectures, and more especially to oligomeriza-
tion processes to access original foldamers.
Experimental Section
General Procedure for the Synthesis of Pyrrolidine-2,4-diones 3a,b:
To a stirred solution of 2a,b (7.00 mmol) in dry THF (30 mL), co-
oled to –78 °C under an atmosphere of argon, was added dropwise
a solution of LiHMDS (1.0 m in THF, 7.00 mmol). After 45 min,
the alkylating agent (7.00 mmol) was added. The reaction was left
at room temperature overnight. The mixture was then diluted with
AcOEt (20 mL) and washed with 0.1 n HCl (10 mL). The organic
center fashioned during the TRAL/alkylation, whereas the layer was then dried with MgSO4 and concentrated in vacuo. The
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T. Coursindel, J. Martinez, I. Parrot
SHORT COMMUNICATION
[8] S. G. Davies, R. L. Sheppard, A. D. Smith, J. E. Thomson,
Chem. Commun. 2005, 3802–3804.
[9] T. A. Martinek, G. K. Tóth, E. Vass, M. Hollósi, F. Fülöp,
Angew. Chem. 2002, 114, 1794; Angew. Chem. Int. Ed. 2002,
41, 1718–1721.
crude mixture obtained was purified by column chromatography
(petroleum ether/AcOEt) to provide the desired pyrrolidine-2,4-di-
one.
General Procedure for the Chemoselective Monodeprotection of Pyr-
rolidine-2,4-diones 3a,b: To a solution of 3a,b (100 mg, 0.21 mmol)
in dichloromethane (5 mL) was added dropwise trifluoroacetic acid
(0.15 mL) at 0 °C. The reaction mixture was stirred for 2.5 h at
0 °C. The reaction media was then evaporated to dryness, and the
remaining TFA was co-evaporated with toluene to afford the corre-
sponding monodeprotected compound 4a,b.
[10] C. Cativiela, M. Ordonez, Tetrahedron: Asymmetry 2009, 20,
1–63.
[11] M. Ordonez, C. Cativiela, Tetrahedron: Asymmetry 2007, 18,
3–99.
[12] M. Rodriguez, P. Fulcrand, J. Laur, A. Aumelas, J. P. Bali, J.
Martinez, J. Med. Chem. 1989, 32, 522–528.
[13] B. L. Iverson, Nature 1997, 385, 113–114.
[14] D. Seebach, S. Abele, K. Gademann, B. Jaun, Angew. Chem.
1999, 111, 1700; Angew. Chem. Int. Ed. 1999, 38, 1595–1597.
[15] G. Guichard, S. Abele, D. Seebach, Helv. Chim. Acta 1998, 81,
187–206.
[16] D. Seebach, M. Overhand, F. N. M. Kuhnle, B. Martinoni, L.
Oberer, U. Hommel, H. Widmer, Helv. Chim. Acta 1996, 79,
913–941.
[17] S. Abele, D. Seebach, Eur. J. Org. Chem. 2000, 1–15.
[18] M. J. I. Andrews, A. B. Tabor, Tetrahedron 1999, 55, 11711–
11743.
[19] Y. Hamuro, J. P. Schneider, W. F. DeGrado, J. Am. Chem. Soc.
1999, 121, 12200–12201.
[20] E. Abraham, S. G. Davies, A. J. Docherty, K. B. Ling, P. M.
Roberts, A. J. Russell, J. E. Thomson, S. M. Toms, Tetrahedron:
Asymmetry 2008, 19, 1356–1362.
[21] M. E. Bunnage, S. G. Davies, R. M. Parkin, P. M. Roberts,
A. D. Smith, J. M. Withey, Org. Biomol. Chem. 2004, 2, 3337–
3354.
[22] L. Kiss, F. Fülöp, Synlett 2010, 1302–1314.
[23] G. Benedek, M. Palko, E. Weber, T. A. Martinek, E. Forro, F.
Fülöp, Eur. J. Org. Chem. 2008, 3724–3730.
[24] G. Benedek, M. Palko, E. Weber, T. A. Martinek, E. Forro, F.
Fülöp, Tetrahedron: Asymmetry 2009, 20, 2220–2225.
[25] S. G. Davies, D. Diez, S. H. Dominguez, N. M. Garrido, D.
Kruchinin, P. D. Price, A. D. Smith, Org. Biomol. Chem. 2005,
3, 1284–1301.
General Procedure for the Tandem Conjugate Addition/Aldol Reac-
tion: A solution of ε-oxo-α,β-unsaturated ester 4a,b (0.90 mmol)
and freshly distilled benzylamine (8.99 mmol) in absolute ethanol
(20 mL) was heated at reflux for 96 h. After evaporation of the
solvent under reduced pressure, the excess amount of benzylamine
was removed by using the 4-benzyloxybenzaldehyde polystyrene as
polymer-supported scavenger reagent following the procedure de-
scribed below: 4-benzyloxybenzaldehyde polystyrene (24.27 g,
11.56 mmol, 2.10 mmol/g) and dichloromethane (30 mL) were
added to the crude mixture, and the reaction mixture was left to
slowly shake at reflux for 3 h. The reaction mixture was then fil-
tered and the resin washed with dichloromethane (3ϫ30 mL) and
methanol (3ϫ30 mL). The filtrate was evaporated in vacuo. The
crude mixture obtained was purified by column chromatography
(dichloromethane/MeOH), providing the desired 2 diastereoiso-
mers 5a_1/5b_1 and 5a_2/5b_2 (respectively ≈6:1).
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data for all compounds (including NMR as-
signments and HRMS).
Acknowledgments
[26] L. Kiss, E. Forro, R. Sillanpaa, F. Fülöp, Tetrahedron 2010, 66,
3599–3607.
We thank the Ministère de l’Enseignement Supérieur et de la Re-
cherche for financial support of this work (T.C.). The authors
thank Axel Roy for his technical assistance.
[27] Y. Matsushima, J. Kino, Eur. J. Org. Chem. 2009, 1619–1624.
[28] A. Joosten, E. Lambert, J. L. Vasse, J. Szymoniak, Org. Lett.
2010, 12, 5128–5131.
[29] T. Uyehara, N. Shida, Y. Yamamoto, J. Chem. Soc., Chem.
Commun. 1989, 113–114.
[1] F. Fülöp, T. A. Martinek, G. K. Toth, Chem. Soc. Rev. 2006,
35, 323–334.
[30] T. Uyehara, N. Shida, Y. Yamamoto, J. Org. Chem. 1992, 57,
3139–3145.
[2] A. Kuhl, M. G. Hahn, M. Dumic, J. Mittendorf, Amino Acids
2005, 29, 89–100.
[3] T. Iwamoto, E. Tsujii, M. Ezaki, A. Fujie, S. Hashimoto, M.
Okuhara, M. Kohsaka, H. Imanaka, K. Kawabata, Y. Inam-
oto, K. Sakane, J. Antibiot. 1990, 43, 1–7.
[4] K. Kawabata, Y. Inamoto, K. Sakane, T. Iwamoto, S. Hashim-
oto, J. Antibiot. 1990, 43, 513–518.
[5] M. Konishi, M. Nishio, K. Saitoh, T. Miyaki, T. Oki, H. Kawa-
guchi, J. Antibiot. 1989, 42, 1749–1755.
[31] N. Shida, T. Uyehara, Y. Yamamoto, J. Org. Chem. 1992, 57,
5049–5051.
[32] D. Farran, I. Parrot, J. Martinez, G. Dewynter, Angew. Chem.
2007, 119, 7632; Angew. Chem. Int. Ed. 2007, 46, 7488–7490.
[33] D. Farran, I. Parrot, L. Toupet, J. Martinez, G. Dewynter, Org.
Biomol. Chem. 2008, 6, 3989–3996.
[34] T. Coursindel, D. Farran, J. Martinez, G. Dewynter, Tetrahe-
dron Lett. 2008, 49, 906–909.
[35] T. Coursindel, A. Restouin, G. Dewynter, J. Martinez, Y. Col-
lette, I. Parrot, Bioorg. Chem. 2010, 38, 210–217.
Received: April 28, 2011
[6] T. Oki, M. Hirano, K. Tomatsu, K. I. Numata, H. Kamei, J.
Antibiot. 1989, 42, 1756–1762.
[7] F. Fülöp, Chem. Rev. 2001, 101, 2181–2204.
Published Online: July 15, 2011
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