Introduction of 4(S)-oxazolidineacetic acid, 2-oxo (D-Oxac) motif in a polypeptide chain: Synthesis and conformational analysis

Article abstract of DOI:10.1039/b210725m

A four step synthesis of 4(S)-oxazolidineacetic acid, 2-oxo benzyl ester (D-Oxac-OBn) from L-Asp-OH in 45% overall yield is reported. The formation of by-products is completely avoided, by microwave irradiation and by the use of caesium carbonate as base. Moreover the synthesis and IR and ¹H NMR conformational analysis of the tetramers Boc-L-Val-D-Oxac-L-Ala-OBn and Boc-L-Val-D-Oxac-Aib-L-Ala-OBn in solution is reported.

Full text of DOI:10.1039/b210725m

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Introduction of 4(S )-oxazolidineacetic acid, 2-oxo (D-Oxac) motif
in a polypeptide chain: synthesis and conformational analysis
Gianluigi Luppi, Marzia Villa and Claudia Tomasini*
Dipartimento di Chimica “G. Ciamician”, Alma Mater Studiorum – Università di Bologna,
Via Selmi, 2-40126 Bologna, Italy
Received 30th October 2002, Accepted 18th November 2002
First published as an Advance Article on the web 19th December 2002
A four step synthesis of 4(S)-oxazolidineacetic acid, 2-oxo
benzyl ester (D-Oxac-OBn) from L-Asp-OH in 45% overall
yield is reported. The formation of by-products is com-
pletely avoided, by microwave irradiation and by the use of
caesium carbonate as base. Moreover the synthesis and IR
1
and H NMR conformational analysis of the tetramers
Boc-L-Val-D-Oxac-L-Ala-OBn and Boc-L-Val-D-Oxac-Aib-
L-Ala-OBn in solution is reported.
Introduction
Fig. 2 Retrosynthesis of Boc--Val--Oxac-Gly--Ala-OBn 1a and of
Boc--Val--Oxac-Aib--Ala-OBn 1b from Z--Asp-OH.
The synthesis of conformationally constrained amino acids is
an important tool for the preparation of oligomers that assume
a well defined secondary structure, such as helices, sheets and
turns.1 The conformational preferences of these molecules are
indeed strongly influenced by structural constraints present in
the monomers, such as tetrasubstituted α-amino acids,2 cyclic
α- and β-amino acids.3 Furthermore new polymeric backbones
with specific folding propensities (‘foldamers’)4 have been
proposed as the first stage in facilitating the design of entirely
synthetic systems with a tertiary structure.5
which in turn was prepared from Z--Asp-OH, using a known
procedure.11 For our purpose, we envisaged an efficient syn-
thesis of the benzyl ester 2 by means of a four step preparation
from Z--Asp-OH (Scheme 1).12
We have recently described the synthesis of oligomers of
(4S,5R)-4-methyl 5-carboxybenzyloxazolidin-2-ones (-Oxd)6
and -pyroglutamic acid (-pGlu)7 and we have demonstrated
that these molecules fold in ordered structures characterized by
a semi-extended helical conformation, analogous to polyproline
II8 and do not exhibit the amide cis–trans dynamic equilibrium
typical of the related poly (-Pro)n I
II helices.8 This effect is
due to the presence of an imidic bond which always adopts only
the trans conformation, even in the dimer. A typical effect of
this behaviour is that the Hα chemical shift of the amino acid
nearby is strongly deshielded by the N-acyl derivative (Fig. 1).
We have demonstrated that the anomalous chemical shift
Scheme 1 Reagents and conditions: (i) Ac2O (3 equiv.), microwave,
1 min; (ii) NaBH4 (1.5 equiv.), dry THF, rt, 16 h; (iii) Cs2CO3 (3 equiv.),
H2O–acetone (3 : 1 ratio), 4 h, reflux; (iv) BnBr (1.5 equiv.), DMF, rt,
16 h.
value is associated with the occurrence of a weak α–CH. . .O᎐C
᎐
By reaction with neat Ac2O under microwave irradiation
(210 W power, 1 min), Z--Asp-OH was transformed in the
corresponding anhydride, which was reduced to the lactone 3
with NaBH4 in dry THF. This reaction can afford a mixture of
3 and of the corresponding hydroxyacid 4, so pure 3 or a mix-
ture of 3 and 4 was treated with Cs2CO3 (3 equiv.) in water and
acetone (3 : 1 ratio) for 4 hours at reflux, to obtain the caesium
carboxylate 5 in quantitative yield, with the formation of
benzyl alcohol as a side product. The solvents were removed
under reduced pressure, DMF and benzyl bromide were added
and the mixture was stirred at room temperature overnight.13
After flash chromatography H--Oxac-OBn 2 was obtained
pure in 45% overall yield from Z--Asp-OH.14
hydrogen bond.7b
Fig. 1 The trans preferential conformation of the imido group is
shown, with the α–CH. . .O᎐C hydrogen bond.
᎐
As a part of this project, we report here a straightforward
synthesis of 4(S)-oxazolidineacetic acid, 2-oxo benzyl ester
(-Oxac-OBn) from -aspartic acid (-Asp-OH) (Fig. 2) and its
introduction in small oligomers, in order to check if it favours
the formation of a β-turn motif.9
To check whether 4(S)-oxazolidineacetic acid, 2-oxo benzyl
ester 2 (H--Oxac-OBn) favours the formation of a β-turn con-
formation, it was introduced into a short oligomer at the i ϩ 1
position, which is commonly filled by proline15 (Scheme 2).
First, 2 was treated with Boc--Val-OPfp (Pfp = penta-
fluorophenyl) in the presence of N,N-dimethylaminopyridine
(DMAP) and diisopropylethylamine (DIEA), to obtain Boc--
Val--Oxac-OBn 6, which was then hydrogenolysed to the
Results and discussion
A couple of syntheses of 4(S)-oxazolidineacetic acid, 2-oxo
(-Oxac) derivatives have been described,10 by hydrolysis or
alcoholysis of (3S)-[(carbobenzyloxy)amino]-γ-butyrolactone,
1
corresponding acid 7. The H NMR spectra of both 6 and 7
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 4 7 – 2 5 0
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Fig. 3 (a) N–H stretch FT-IR data for the 3 mM sample of 1a in CH2Cl2 at room temperature, after subtraction of the spectrum of pure CH2Cl2;
(b) N–H stretch FT-IR data for the 3 mM sample of 1b in CH2Cl2 at room temperature, after subtraction of the spectrum of pure CH2Cl2; (c) amide
1
1
protons H NMR chemical shift of 1a in CDCl3 as a function of the temperature; (d) amide protons H NMR chemical shift of 1b in CDCl3 as a
function of the temperature.
-Oxd and -pGlu oligomers and is evidence for the stable
anti disposition of the two carbonyl groups of the semi-cyclic
acylurethane system.
The oligomers Boc--Val--Oxac-Gly--Ala-OBn 1a and
Boc--Val--Oxac-Aib--Ala-OBn 1b were prepared by liquid
phase synthesis, introducing respectively glycine and 2-amino-
isobutyric acid (Aib)16 at the i ϩ 2 position. The coupling was
performed with H-Gly--Ala-OBn and H-Aib--Ala-OBn17 to
yield the desired tetramers 1a and 1b, in good yield after silica
gel chromatography.18
The preferential conformations assumed by 1a and1b in solu-
tion of structure supporting solvents were analysed by IR and
1
1H NMR spectroscopy (Fig. 3). The H NMR spectra of both
1a and 1b show that the α-CH chemical shift of the valine
residue resonates at 5.35 and 5.30 ppm respectively, as we
previously observed for Boc--Val--Oxac-OBn 6 and Boc--
Val--Oxac-OH 7, thus showing that the functionalisation of
the carboxy group does not affect the anti disposition of the
two carbonyls of the imido group.
The IR spectrum of 1a19(Fig. 3a) shows the presence of two
peaks at 3429 and 3326 cmϪ1 which can be ascribed to a non-
hydrogen bonded NH amide proton and an hydrogen bonded
NH amide proton respectively. The band at 3326 cmϪ1 is weak,
so possibly an equilibrium between an open form and a turn is
Scheme 2 Reagents and conditions: (i) Boc--Val-OPfp (1.5 equiv.),
going on. The IR spectrum of 1b (Fig. 3b) reports more
DIEA (2.5 equiv.), DMAP (1 equiv.), dry DMF, rt, 16 h; (ii) Pd/C 10%
encouraging results: two comparable bands at 3434 and 3330
(0.1 equiv.), H2 (3 atm), AcOEt, rt, 3 h; (iii) H-Gly--Ala-OBn
cmϪ1 are present. More information on the conformational
(2 equiv.), NMM (4 equiv.), HOBt (1.2 equiv.), EDCI (1.2 equiv.), dry
behaviour of our tetramers were obtained with the examination
of the chemical shift dependence of the amide NH protons on
the temperature in CDCl3 (Figs. 3c–d). This test points out the
presence of hydrogen-bonded amide protons: a small temper-
ature coefficient (≤3 ppb KϪ1 in absolute value) indicates the
presence of an hydrogen-bonded amide proton, while protons
DMF, rt, 16 h; (iv) H-Aib--Ala-OBn (2 equiv.), NMM (4 equiv.),
HOBt (1.2 equiv.), EDCI (1.2 equiv.), dry DMF, rt, 16 h.
show that the α-CH chemical shift of the valine residue is
strongly deshielded by the N-acyl derivative (6: 5.40 ppm and 7:
5.42 ppm). This outcome was previously observed for both our
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 4 7 – 2 5 0
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E. G. Occhiato and A. Guarna, Org. Lett., 2000, 3987; (d ) T. D. W.
which participate to an equilibrium between hydrogen-bonded
and non hydrogen-bonded state show a larger temperature
coefficient.20 Following these criteria, only NH-Val of 1a is
hydrogen-bonded,21 while in 1b both NH-Val and NH-Ala are
hydrogen-bonded amide protons.
This result is in full agreement with the IR spectra, which
show a stronger band of hydrogen-bonded amide protons for
1b than for 1a, and it is quite reasonable, because the introduc-
tion of the Aib moiety as i ϩ 2 amino acid enhances the rigidity
of the whole system. NOESY experiments performed on the
two samples (400 MHz, mixing time 900 ÷ 1,500 msec) furnish
little additional information: 1a shows a cross peak between
NH-Ala and CH2-Gly and another between α-CH-Ala and
CH2-Gly, besides the trivial ones. On the contrary, NOESY
spectra of 1b do not show any cross peak, besides the trivial
ones.
Claridge, J. M. Goodman, A. Moreno, D. Angus, S. F. Barker,
C. Taillefumier, M. P. Watterson and G. W. Fleet, Tetrahedron Lett.,
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6 (a) S. Lucarini and C. Tomasini, J. Org. Chem., 2001, 66, 727;
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7 (a) C. Tomasini and M. Villa, Tetrahedron Lett., 2001, 42, 5211;
(b) F. Bernardi, M. Garavelli, M. Scatizzi, C. Tomasini, V. Trigari,
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2002, 8, 2516.
8 A. J. Hopfinger, in Conformational Properties of Macromolecules,
Academic Press, New York, 1973, pp. 182–189, and references
therein.
All these data, when taken in conjunction, suggest that the
preferential conformation of 1a is somehow more extended and
accommodates αCH hydrogens of Gly and Ala near to one
another; while 1b assumes a preferential β-turn conformation,
with the chelation of NH-Val and NH-Ala (Fig. 4).
9 For some recent examples see: (a) J. D. Fisk, D. R. Powell and
S. H. Gellman, J. Am. Chem. Soc., 2000, 122, 5443; (b) J. M.
Langenhan, J. D. Fisk and S. H. Gellman, Org. Lett., 2001, 3, 2559;
(c) Y. J. Chung, B. R. Huck, L. A. Christianson, H. E. Stanger,
S. Krauthäuser, D. R. Powell and S. H. Gellman, J. Am. Chem. Soc.,
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M. E. B. Smith and S. H. Gellman, J. Am. Chem. Soc., 2001, 123,
11077; (e) C. Gennari, A. Mielgo, D. Potenza and C. Scolastico,
Eur. J. Org. Chem., 1999, 379; ( f ) L. Belvisi, C. Gennari, A. Mielgo,
D. Potenza and C. Scolastico, Eur. J. Org. Chem., 1999, 389;
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E. M. Smith and J. S. Nowick, J. Am. Chem. Soc., 1997, 119, 7665;
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893.
Fig. 4 Preferential conformation assumed by 1b, as it turns out from
10 (a) P. J. Murray and I. D. Starkey, Tetrahedron Lett., 1996, 37, 1875;
(b) D.-C. Ha, K. Kun-Eek, K.-S. Choi and H.-S. Park, Tetrahedron
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IR and 1H NMR analysis.
11 (a) W. B. Lutz, C. Ressler and D. E. Jr. Nettleton, J. Am. Chem. Soc.,
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12 An alternative method for the preparation of oxazolidin-2-ones
from 1,2-amino alcohol benzyl carbamates has recently been
described by a new solid-to-solid process without using any solvents:
G. Li, R. Lenington, S. Willis and S. H. Kim, J. Chem. Soc., Perkin
Trans. 1, 1998, 1753.
In conclusion, we have shown a convenient and straight-
forward method for the synthesis of 4(S)-oxazolidineacetic
acid, 2-oxo benzyl ester (-Oxac-OBn) 2 from commercially
available Z--Asp-OH. Furthermore, by IR and 1H NMR
analysis, we have tested its propensity to induce a β-turn con-
formation to the oligomers Boc--Val--Oxac-Gly--Ala-OBn
1a and Boc--Val--Oxac-Aib--Ala-OBn 1b in a solution of
structure supporting solvents. This molecule is a promising
scaffold for the design and synthesis of libraries of short
oligomers with a well-defined secondary structure.
13 I. Shin, M. Lee, J. Lee, M. Jung, W. Lee and J. Yoon, J. Org. Chem.,
2000, 65, 7667.
14 -Oxac-OBn 2 Mp = 82–83 ЊC; [α]D = Ϫ32.5 (c. 1.0, CH2Cl2); IR:
ν 3240, 1731, 1706 cmϪ1; 1H NMR (CDCl3): δ 2.64 (dd, 1 H, J = 6.2,
17.2 Hz, CHHCO), 2.74 (dd, 1 H, J = 7.8, 17.2 Hz, CHHCO), 4.05
(dd, 1 H, J = 5.4, 8.4 Hz, CHHO), 4.17–4.31 (m, 1 H, CHN), 4.55
(t, 1 H, J = 8.4 Hz, CHHO), 5.15 (s, 2 H, OCH2Ph), 7.37 (s, 5 H, Ph);
13C-NMR (CDCl3) 39.7, 49.0, 67.2, 69.5, 128.7, 135.2, 159.0, 170.4.
15 (a) S. S. Zimmermann and H. A. Scheraga, Biopolymers, 1977,
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16 (a) B. V. V. Prasad, H. Balaram and P. Balaram, Conformation
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P. Balaram, Crit. Rev. Biochem., 1984, 16, 307; (c) R. Kaul and
P. Balaram, Bioorg. Med. Chem., 1999, 7, 105; (d ) C. Toniolo,
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J. Kamphuis, Biopolymers, 1993, 33, 1061.
Acknowledgements
This work was supported in part by MIUR (Cofin 2000 and
60% – Roma) and by Alma Mater Studiorum – University of
Bologna (funds for Selected Research Topics).
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17 The dipeptides H-Gly--Ala-OBn and H-Aib--Ala-OBn were
obtained in liquid phase, following the Boc-OBn protocol. The
coupling agents are NMM, HOBt and EDCI.
3 (a) J. S. Nowick, Acc. Chem. Res., 1999, 32, 287; (b) S. H. Gellman
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5 For examples of novel oligomeric systems recently proposed as
foldamers see: (a) A. J. Zych and B. L. Iverson, J. Am. Chem. Soc.,
2000, 122, 8898; (b) R. Gunther and H.-J. Hofmann, J. Am. Chem.
Soc., 2001, 123, 247; (c) F. Machetti, A. Ferrali, G. Menchi,
18 General method for the synthesis of 1a and 1b: To a stirred solution
of 7 (0.25 mmol, 86 mg) in dry DMF (1 mL) was added H-Gly--
Ala-OBn (0.5 mmol, 118 mg) or H-Aib--Ala-OBn (0.5 mmol, 130
mg), NMM (1 mmol, 0.11 mL), HOBt (0.3 mmol, 58 mg) and EDCI
(0.3 mmol, 40 mg) under argon atmosphere. The mixture was stirred
at room temperature overnight, then diluted with ethyl acetate (20
mL) and washed with aqueous 1 N HCl (2 × 10 mL). The organic
layer was dried over sodium sulfate, concentrated and the residue
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 4 7 – 2 5 0
249

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was chromatographed (cyclohexane–ethyl acetate 7 : 3 as eluant).
Boc--Val--Oxac-Gly--Ala-OBn 1a: Yield 60%; low melting solid;
[α]D = ϩ48.9 (c. = 0.9, CH2Cl2); IR (CH2Cl2): ν 3429, 3323, 1785,
4.62 (m, 1 H, CHN), 4.61 (dd, 1 H, J = 7.2, 9.2 Hz, CHHCO), 4.72–
4.86 (m, 1 H, CHN), 5.09 (d, 1 H, J = 8.0 Hz, NH), 5.17 (AB, 2 H,
J = 12.2 Hz, OCH2Ph), 5.30 (dd, 1 H, J = 4.8, 8.0 Hz, CHN), 6.90
(br s, 2 H, NH ϩ NH), 7.25–7.40 (m, 5 H, Ph); 13C NMR (CDCl3):
δ 17.0, 18.4, 19.9, 25.0, 25.6, 28.6, 30.0, 38.6, 48.6, 52.1, 57.8, 67.3,
67.8, 80.7, 128.4, 128.8, 135.3, 150.2, 153.2, 169.0, 173.5, 173.8,
182.3.
1733, 1693 cmϪ1 1H NMR (CDCl3): δ 0.88 (d, 3 H, J = 6.6 Hz,
;
Me), 1.04 (d, 3 H, J = 6.6 Hz, Me), 1.43 (s, 9 H, t-Bu), 1.68 (d, 3 H,
J = 7.1 Hz, Me), 2.05–2.18 (m, 1H, CHMe2), 2.68 (dd, 1 H, J = 8.7,
15.1 Hz, CHHCO), 2.84 (dd, 1 H, J = 2.3, 15.1 Hz, CHHCO), 3.93
(ABX, 2 H, J = 5.4, 5.7, 16.8 Hz, CH2N), 4.40–4.52 (m, 2 H, CH2O),
4.63 (dq J = 7.5 Hz, CHN), 4.74–4.84 (m, 1 H, CHN), 5.14 (br s, 1 H,
NH), 5.17 (AB, 2 H, J = 12.3 Hz, OCH2Ph), 5.29–5.38 (m, 1 H,
CHN), 6.77 (br s, 1 H, NH), 7.07 (br s, 1 H, NH), 7.30–7.39 (m, 5 H,
Ph); 13C NMR (CDCl3): δ 16.6, 18.2, 19.6, 28.3, 29.9, 37.8, 43.4,
48.3, 51.9, 57.6, 67.2, 80.4, 128.1, 128.4, 128.6, 135.3, 152.7, 156.2,
168.1, 169.5, 172.5, 173.3. Boc--Val--Oxac-Aib--Ala-OBn 1b:
Yield 65%; mp = 59–63 ЊC; [α]D = ϩ56.5 (c. = 0.2, CH2Cl2); IR
19 The IR absorption spectra were obtained as 3 mM solutions in
methylene chloride: at this concentration the intramolecular aggre-
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(CH2Cl2): ν 3434, 3330, 1782, 1734, 1696, 1683 cmϪ1 1H NMR
;
(CDCl3): δ 0.91 (d, 3 H, J = 7.0 Hz, Me), 1.06 (d, 3 H, J = 7.0 Hz,
Me), 1.42 (d, 3 H, J = 7.0 Hz, Me), 1.44 (s, 9 H, t-Bu), 1.51 (s, 3 H,
Me), 1.54 (s, 3 H, Me), 2.02–2.22 (m, 1 H, CH(Me)2), 2.58–2.70
(m, 2 H, CH2CO), 4.43 (dd, 1 H, J = 8.4, 9.2 Hz, CHHCO), 4.52–
21 Y. V. Venkatachalapathi, C. M. K. Nair, M. Vijayan and P. Balaram,
Biolpolymers, 1981, 20, 1123.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 4 7 – 2 5 0
250