Stereodivergent syntheses of the first bis(cyclobutane) β-dipeptides

Article abstract of DOI:10.1016/S0957-4166(02)00652-3

The efficient synthesis of methyl 2-benzyloxycarbonylamino-(1S,2R)-cyclobutane-1-carboxylate starting from 2-methoxycarbonyl-(1R,2S)-cyclobutane-1-carboxylic acid is described. This β-amino acid derivative is antipodal with respect to the (1R,2S)-compound

Full text of DOI:10.1016/S0957-4166(02)00652-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2403–2405
Stereodivergent syntheses of the first bis(cyclobutane)
b-dipeptides
Sandra Izquierdo, Marta Mart´ın-Vila`, Albertina G. Moglioni,† Vicenc¸ Branchadell and
Rosa M. Ortun˜o*
Departament de Qu´ımica, Universitat Auto`noma de Barcelona, 08193 Bellaterra, Barcelona, Spain
Received 26 September 2002; accepted 10 October 2002
Abstract—The efficient synthesis of methyl 2-benzyloxycarbonylamino-(1S,2R)-cyclobutane-1-carboxylate starting from 2-
methoxycarbonyl-(1R,2S)-cyclobutane-1-carboxylic acid is described. This b-amino acid derivative is antipodal with respect to the
(1R,2S)-compound that was previously synthesized in our laboratory from the same chiral hemi ester. In turn, these enantiomeric
b-amino acids have been self-condensed and coupled with one another to provide, respectively, enantiomeric and diastereomeric
bis(cyclobutane) b-dipeptides. These products are the first reported b-amino acid oligomers containing two directly linked
cyclobutane residues. © 2002 Elsevier Science Ltd. All rights reserved.
b-Peptides have attracted the particular attention of
scientists in recent years since their ability to produce
secondary structures, i.e. helixes, turns, and sheets, was
established.1,2 In general, the number of residues
required to form these structures in a b-peptide is lower
than in a peptide formed from a-amino acids.3 Another
advantage is that their resistance to enzymatic hydroly-
sis is also enhanced with respect to the a-peptides.1a,4
Therefore, these properties are being considered in
order to develop new therapeutic agents.5 Very recently,
amphiphilic b-amino acid oligomers that mimic the
properties of defence peptides have been designed and
synthesized by the group of Gellman.6 Their antibiotic
activity against several bacterial species, some of them
being resistant to common antibiotics, has been shown.
condensed with one b-alanine residue to afford a b-
dipeptide whose structural study showed a hairpin-like
conformation in the solid state.9 The starting material
in that synthesis was hemi ester 1, prepared through
chemoenzymatic hydrolysis of the corresponding meso-
dimethyl ester. In this way, amino acid derivative (−)-2
was prepared in 91% e.e. as determined by HPLC using
chiral stationary phases.
In this communication, we describe the synthesis of the
enantiomeric cyclobutane b-amino acid derivative, (+)-
2, from the same chiral precursor, 1 (Scheme 1). Self-
coupling of the conveniently-protected enantiomeric
amino acids, as well as one with another, provides a
stereodivergent
route
to
enantiomeric
and
diastereomeric bis(cyclobutane) b-dipeptides. We
described herein dipeptides (−)-5, (+)- and (−)-10, which
are representative examples of the firstly synthesized
title compounds.
Regarding the peptides bearing carbocyclic moieties, it
is noteworthy that, to the best of our knowledge,
although studies on some cyclobutane a-amino acid
oligomers have been reported7 there are no precedents
on cyclobutane b-peptides prior to our work.
Acid (−)-4 was prepared quantitatively by treatment of
(−)-2 with a 0.25 M aqueous NaOH solution in (1:10)
THF/H2O at 0°C for 1 h. Epimerisation of the stereo-
genic centres was avoided under such mild conditions.10
This acid was condensed with amine (−)-3, resulting
from hydrogenolysis of the benzyl carbamate (−)-2, in
the presence of excess 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide (DEC) as dehydrating agent and 1
equiv. of 1-hydroxybenzotriazole (HOBt) as a catalyst,
Recently, we described the synthesis of an orthogonally
protected cyclobutane b-amino acid, (−)-2 (Scheme
1),8,9 that was converted into the free acid (−)-4 and
* Corresponding author. E-mail: rosa.ortuno@uab.es
† Present address: Departamento de Qu´ımica Orga´nica, Facultad de
Farmacia y Bioqu´ımica, Universidad de Buenos Aires, 1113 Buenos
Aires, Argentina.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00652-3

2404
S. Izquierdo et al. / Tetrahedron: Asymmetry 13 (2002) 2403–2405
Scheme 1.
tively. The acyl azide 8 was prepared in 91% yield by
reaction of 7 with ethyl chloroformate in acetone at 0°C
for 3 h, followed by treatment with sodium azide for 2
h. Subsequently, Curtius rearrangement was achieved
by heating 8 for 3.5 h in the presence of excess benzyl
alcohol in refluxing toluene solution to give the fully
protected b-amino acid 9. In order to verify the
opposed chirality of this compound with respect to
(−)-2, the tert-butyl ester was replaced by a methyl
ester. For this purpose, 9 was made to react with
in anhydrous DMF at room temperature for 20 h. In
this way, fully protected b-dipeptide (−)-5 was obtained
as a viscous oil, [h]D −108.11
In order to synthesize the enantiomers (+)- and (−)-10,
amino acid derivative (+)-2 was prepared as follows.
Hemi ester
1
was treated with tert-butyl
trichloroacetimidine12 in dichloromethane at room tem-
perature for 20 h to afford diester 6 in 90% yield. The
methyl ester was selectively hydrolysed as described
above to produce the tert-butyl hemi ester 7 quantita-
trifluoroacetic
acid
and
triethylsilane13
in

S. Izquierdo et al. / Tetrahedron: Asymmetry 13 (2002) 2403–2405
2405
dichloromethane at room temperature for 2 h to
provide acid (+)-4 quantitatively. Esterification with
diazomethane gave the methyl ester (+)-2, [h]D +83 (lit.9
2. DeGrado, W. F.; Schneider, J. P.; Hamuro, Y. J. Pept.
Res. 1999, 54, 206.
3. Appella, D.; Christianson, L. A.; Klein, D. A.; Richards,
M. R.; Powell, D. R.; Gellman, S. H. J. Am. Chem. Soc.
1996, 121, 7574.
4. (a) Hintermann, T.; Seebach, D. Synlett 1977, 437; (b)
Seebach, D.; Abele, S.; Schreiber, J. V.; Martinoni, B.;
Nussbaum, A. K.; Schild, H.; Schulz, H.; Hennecke, H.;
Woessner, R.; Bitsch, F. Chimia 1998, 52, 734.
5. For recent reviews, see: (a) Cheng, R. P.; Gellman, S. H.;
DeGrado, W. F. Chem. Rev. 2001, 3219; (b) Steer, D. L.;
Lew, R. A.; Perlmutter, P.; Smith, A. I.; Aguilar, M.-I.
Curr. Med. Chem. 2002, 9, 811.
1
[h]D −83 for the enantiomer) whose H and 13C NMR
spectra were fairly superimposed on those of (−)-2.
Hydrogenolysis of (+)-2 gave the free amine (+)-3 that
was condensed with acid (−)-4, under the conditions
described above, to produce b-dipeptide (−)-10, [h]D
−63, in 79% yield.
In the same way, amine (−)-3 was coupled with acid
(+)-4 to furnish the enantiomeric b-dipeptide (+)-10,
[h]D +62, in 72% yield.
6. Porter, E. A.; Weisblum, B.; Gellman, S. H. J. Am.
Chem. Soc. 2002, 124, 7324.
7. Gatos, M.; Formaggio, F.; Crisma, M.; Toniolo, C.;
Bonora, G. M.; Benedetti, Z.; Di Blasio, B.; Iacovino, R.;
Santini, A.; Saviano, M.; Kamphuis, J. J. Pept. Sci. 1997,
3, 110.
Thus, from a single chiral precursor, enantiomeric
cyclobutane b-amino acids have been synthesized and,
in turn, these compounds have been incorporated into
enantiomeric or diastereomeric b-dipeptides containing
two directly linked cyclobutane residues. These
molecules are highly constrained and their structural
and conformational study, by using experimental tech-
niques and theoretical calculations, is under current
investigation in our laboratory.
8. Mart´ın-Vila`, M.; Minguillo´n, C.; Ortun˜o, R. M. Tetra-
hedron: Asymmetry 1998, 9, 4291.
´
9. Mart´ın-Vila`, M.; Muray, E.; Aguado, G. P.; Alvarez-
Larena, A.; Branchadell, V.; Minguillo´n, C.; Giralt, E.;
Ortun˜o, R. M. Tetrahedron: Asymmetry 2000, 11, 3569.
10. Niwayama, S. J. Org. Chem. 2000, 65, 5834.
11. All new products were identified and fully characterized
by their spectroscopic data and physical constants.
Selected data follow. Compound 5: viscous oil, [h]D −108
(c 1.79, MeOH); compound 6: oil, [h]D +4.0 (c 0.50,
MeOH); compound 7: oil, [h]D +9.3 (c 1.08, MeOH);
compound 9: oil, [h]D +41 (c 0.42, CHCl3); compound
(+)-2: oil, [h]D +83 (c 0.70, CHCl3) [lit.,10 [h]D −83 (c 2.05,
CHCl3)]; compound (+)-10: pasty solid, [h]D +62 (c 0.44,
MeOH); compound (−)-10: pasty solid, [h]D −63 (c 1.59,
MeOH).
Acknowledgements
S.I. thanks the UAB for a predoctoral fellowship.
Financial support from DGI (MCyT) through the pro-
ject BQU2001-1907 is gratefully acknowledged.
References
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