β-Pseudopeptide foldamers. the homo-oligomers of (4R)-(2-oxo-1,3-oxazolidin-4-yl)-acetic acid (D-Oxac)

Article abstract of DOI:10.1039/b405856a

A total synthesis in solution and a conformational analysis of the homo-oligomers of (4R)-(2-oxo-1,3-oxazolidin-4-yl)-acetic acid (D-Oxac) to the tetramer level are described. As the D-Oxac building block contains both an oxazolidin-2-one and a β-amino acid group, it may represent a new type of conformationally constrained tool for the construction of β-pseudopeptide foldamers. A conformational investigation using NMR and an extensive, unconstrained analysis with a Monte Carlo search to the octamer level, both in water and in chloroform, showed that these homo-oligomers tend to fold in a regular helical structure in a competitive solvent, such as water. Since aqueous solutions are of major relevance for biological systems, these molecules are good candidates for application to these environments.

Full text of DOI:10.1039/b405856a

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A R T I C L E
-Pseudopeptide foldamers. The homo-oligomers of (4R)-
(2-oxo-1,3-oxazolidin-4-yl)-acetic acid (D–Oxac)
Gianluigi Luppi,a Roberta Galeazzi,b Marco Garavelli,a Fernando Formaggioc and
Claudia Tomasini*a
a
Department of Chemistry “G. Ciamician”, Alma Mater Studiorum, University of Bologna,
40126 Bologna, Italy. E-mail: claudia.tomasini@unibo.it; Fax: +39 0512099456;
Tel: +39 0512099511
Università Politecnica delle Marche, Department of Material and Earth Sciences,
b
60131 Ancona, Italy. E-mail: roberta@mta01.univpm.it; Fax: +39 0712204714;
Tel: +39 0712204724
Institute of Biomolecular Chemistry, CNR, Department of Chemistry, University of Padova,
c
35131 Padova, Italy. E-mail: fernando.formaggio@unipd.it; Fax: +39 0498275239;
Tel: +39 0498275277
Received 20th April 2004, Accepted 10th June 2004
First published as an Advance Article on the web 14th July 2004
A total synthesis in solution and a conformational analysis of the homo-oligomers of (4R)-(2-oxo-1,3-oxazolidin-4-yl)-
acetic acid (D–Oxac) to the tetramer level are described. As the D–Oxac building block contains both an oxazolidin-2-
one and a -amino acid group, it may represent a new type of conformationally constrained tool for the construction of
-pseudopeptide foldamers. A conformational investigation using NMR and an extensive, unconstrained analysis with a
Monte Carlo search to the octamer level, both in water and in chloroform, showed that these homo-oligomers tend to fold
in a regular helical structure in a competitive solvent, such as water. Since aqueous solutions are of major relevance for
biological systems, these molecules are good candidates for application to these environments.
Introduction
In the last few years the design and synthesis of oligomers based
on -amino acids have been extensively carried out, both in the
presence and absence of stabilising hydrogen bonds.1 Non-hydrogen
bonded secondary structures, for example, poly(Pro)n helices,
occur occasionally in proteins and in short peptides. Individual
strands within the collagen triple helix are folded in a poly(Pro)n
Fig. 1 Preferred conformation of the side chain of the acylated L–pGlu
II (PPII) conformation. Short PPII helices play important roles in
protein-protein recognition. Seebach and coworkers2 have studied
oligomers of -HPro-peptides and have demonstrated that this class
of -peptides may still adopt distinct folding patterns due to the
high intrinsic folding propensity of the -peptide backbone. More
recently, Gellman and coworkers3 have studied the oligomers of 2,2-
disubstituted-pyrrolidine-4-carboxylic acid (2,2-DPCA) and have
demonstrated that these compounds display well defined conforma-
tional preferences, although they cannot form hydrogen bonds.
We have recently introduced pseudopeptides based on an -
amino acid cyclic derivatives (Pro analogues) as building blocks
where the classical amide bonds are replaced by imide bonds.
More specifically, oligomers of substituted 1,3-oxazolidin-2-ones
(L–Oxd)4 and -lactams (L–pGlu)5 have been examined. These
studies have demonstrated that these oligomers adopt a semi-
extended secondary structure similar to that of poly(Pro)n II even
in the dimer and that conformational equilibria are not operative.
In these molecules hydrogen bonds are missing and the stabilizing
effect is due to the imide moiety, which always adopts a conforma-
tion with the two carbonyls in the anti disposition (Fig. 1).
(R = H, X = CH2) and L–Oxd (R = Me, X = O) rings. The disposition of the
imide moiety, which is due to the tendency of the two carbonyls to repel each
other, is further stabilized by formation of a COH–C hydrogen bond,
with an energetic contribution of approximately 1.4 kcal mol−1.4,5
Fig. 2 Chemical structure of the longest D–Oxac homo-oligomer
investigated in this work.
“rotatable” bond in the backbone. Indeed it has been demonstrated
that -peptides can form stable helices with only four to six residues,
whereas an -peptide of that length would be disordered.3
Results and discussion
Synthesis of oligomers
The synthesis of the monomer H–D–Oxac–OBn (2) (Scheme 1) has
already been described.7,8 It involves the transformation of Z–L–
Asp–OH into its corresponding internal anhydride by reaction with
neat acetic anhydride under microwave irradiation. The product was
obtained in quantitative yield and was subsequently reduced to the
lactone 1 with NaBH4 in dry THF. This reaction can afford a mixture
of 1 and the corresponding -hydroxy acid, which however are both
starting materials for the cyclization reaction to the oxazolidin-2-
one 2. Therefore, either pure 1 or a mixture of 1 and its hydroxy acid
was treated with Cs2CO3 (3 equivalents) in water and acetone (3:1
ratio) for 4 h at reflux to obtain the caesium salt of the oxazolidin-2-
one acetate (H–D–Oxac–O−Cs+), with formation of benzyl alcohol
In this article, we describe our synthetic and conformational
results obtained with oligoimides where the single unit is a -amino
acid cyclic derivative, (4R)-(2-oxo-1,3-oxazolidin-4-yl)-acetic acid
(D–Oxac). These homo-oligomers are expected to adopt more
flexible structures than those characteristic of their -amino acid
counterparts, although they still contain imide moieties (Fig. 2).
Nevertheless, we will show here that these molecules fold in
ordered helical 3D-structures, in polar solvents.
These oligomers afford similar results to what observed with
-peptides,6 which surprisingly have exhibited greater conforma-
tional stability than -peptides, although they provide an additional
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 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 1 8 1 – 2 1 8 7
2 1 8 1

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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.9 After flash chromato-
graphy H–D–Oxac–OBn 2 was obtained pure in 45% overall yield
from Z–L–Asp–OH. We chose the acetyl as an appropriate blocking
group for the N-terminal D–Oxac unit, because of its high polarity.
Indeed, our aim was the synthesis of significantly polar and hope-
fully water soluble -pseudopeptide oligomers.
Table 1 CH proton chemical shifts of the Ac–(D–Oxac)n–OBn (n = 1–4)
homo-oligomers in CDCl3 solution
Chemical shifts in CDCl3 solution (400 MHz)
Entry
Compound
-CH2
-CH2
-CH2
-CH2
ring A
ring B
ring C
ring D
1
2
2
6
—
—
—
—
—
2.74
and 3.14
2.74
3.20
and 3.63
and 3.14
3
4
9
—
3.27 and 3.52–3.64
2.74
and 3.10
12
3.25–3.38 and 3.50–3.68
2.74
and 3.12
Table 2 CH proton chemical shifts of the Ac–(D–Oxac)n–OBn (n = 1–4)
homo-oligomers in CDCl3 solution
Chemical shifts in CDCl3 solution (400 MHz)
Entry
Compound
-CH
-CH
-CH
-CH
ring A
ring B
ring C
ring D
1
2
3
4
2
6
9
—
—
—
4.84
—
—
4.84
4.84
—
4.78
4.74
4.74
4.76
4.85
4.84
4.84
Scheme 1 Reagents and conditions: (i) Ac2O (3 equiv.), microwave
(1 min.); (ii) NaBH4 (1.1 equiv.), THF, room temperature, 16 h; (iii) Cs2CO3
(2 equiv.), acetone/water 1:3, reflux, 3 h; (iv) BnBr (1.1 equiv.), room
temperature, 2 h; (v)AcCl (1.1 equiv.), DIEA(3 equiv.), DMAP (0.5 equiv.),
dry DMF, room temperature, 24 h; (vi) Pd/C 5% (10% w/w), H2 (2 atm.),
MeOH, room temperature, 1 h; (vii) CF3CO2Pfp (1.3 equiv.), pyridine
(2 equiv.), dry DMF, room temperature, 1 h; (viii) DIEA (4 equiv.), DMAP
(0.5 equiv.), dry DMF, room temperature, 24 h.
12
C–HOC interaction is clearly absent for the C-terminal CH
proton, that therefore resonates in the expected spectral region.
A similar effect has been also observed for the -protons
(Table 2). However, in this case it is much weaker as a variation of
only about 0.1 ppm is found.
The synthesis of the homo-oligomers was achieved in liquid
phase, by transformation of the acids 4, 7 and 10 into the corres-
ponding pentafluorophenyl esters 5, 8 and 11, following a well
established procedure.10 The activated esters were then coupled
with H–D–Oxac–OBn 2 in the presence of DIEA and DMAP in
DMF. A variety of other bases were tested in this coupling reac-
tion (including DBU and triethylamine), but the best results were
obtained with a mixture of DIEA (3 equivalents) and DMAP (0.5
equivalents). Using this approach, dimerAc–(D–Oxac)2–OR, trimer
Ac–(D–Oxac)3–OR and tetramerAc–(D–Oxac)4–OR (R = Bn or H)
were obtained, both as benzyl esters and as free acids, by repeating
the following reactions: benzyl group removal, transformation of
the free acid into the activated ester, and coupling with H–D–Oxac–
OBn 2. Upon formation of the longest oligomers, we obtained com-
pounds of progressively higher water solubility.
This different behaviour of the C-terminal residue cannot be
ascribed to a mere stereoelectronic effect, due to the C-terminal
carboxyl derivative being an ester rather than an imide (as in the case
of the first three residues). Indeed, the CH protons of residue D
should be more deshielded than the CH protons of residuesA–C in
view of the highest electrowithdrawing power of the oxygen (ester)
as compared to that of the nitrogen (imide). For instance the methyl
group of N-ethyl acetamide resonates as a singlet at 1.98 ppm, in
CDCl3, while the methyl group of ethyl acetate resonates in CDCl3
at 2.04 ppm. Moreover, we have recently synthesized two tetra-
peptides, containing the D–Oxac ring, that assume preferentially a
-turn conformation: Boc–L–Val–D–Oxac–Gly–L–Ala–OBn and
Boc–L–Val–D–Oxac–Gly–L–Ala–OBn.7 In both cases the CH
protons of the D–Oxac moiety resonate between 2.65 and 2.85 ppm,
so they are nearly 1 ppm more shielded in comparison with the CH
proton of rings A, B and C.
Conformational analysis of oligomers
In conclusion, both - and -protons of each D–Oxac oligomer
are affected by the presence of the endocyclic carbonyl. Thus, a
reasonable preferred conformation should invoke an anti disposition
for the two carbonyls.
An experimental investigation of the preferred conformation
assumed by Ac–(D–Oxac)n–OBn (n = 1–4) oligomers in CDCl3
solution was performed using 1H NMR. The chemical shifts of the
-protons of the four oligomers are reported in Table 1. We can see
that the -protons of rings A, B and C of compounds (6), (9) and
(12) have chemical shifts that are more deshielded of about 0.5 ppm
if compared to those of ring D. Clearly, this is a general effect as it
has been previously observed in all of the pseudopeptides containing
oxazolidin-2-ones or -lactam rings.4,5 We have previously
demonstrated that this unusual shift is due to the presence of an
endocyclic carbonyl in a close proximity to the CH protons.4,5
Indirectly, from the present data we deduce that the two carbonyls of
the D–Oxac oligomers are forced to adopt an anti disposition. This
With the aim of confirming these experimental results and in
particular to obtain a better insight into the conformational prefer-
ence of the Ac/OBn D–Oxac tetramer in a 3D-structure supporting
solvents (chloroform) and in a competitive solvent (water) as well,
an extensive unconstrained conformational analysis was performed
by varying all of the degrees of freedom using the Monte Carlo11
conformational search (MC/EM), the OPLS* force field12 for en-
ergy calculation and the GB/SA both in water and chloroform to
include the solvent effect.13 All of the conformers within the energy
range of 25 kJ mol−1 (about 6 kcal mol−1) were considered, but sub-
2 1 8 2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 1 8 1 – 2 1 8 7

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Table 3 Calculated energy (in kcal mol−1) and “φ”/”” (in °) values for all of the conformers of Ac–(D–Oxac)4–OBn 12 within 2 kcal mol−1 in water
Conformer entry
Energy /kcal mol−1
“φ1”
“1”
“φ2”
“2”
“φ3”
“3”
“φ4”
“4”
1
2
3
4
5
6
7
8
9
10
11
12
13
14
0.00
0.66
0.69
0.73
0.85
1.04
1.16
1.22
1.56
1.60
1.83
1.86
1.94
1.95
71.9
70.9
72.0
71.8
68.7
71.9
76.1
72.1
71.8
71.9
72.3
71.1
71.8
74.5
8.0
4.5
8.1
7.4
−8.1
8.0
4.0
8.5
7.7
8.1
9.9
5.7
7.8
−1.7
71.5
70.7
69.4
71.3
63.9
70.7
63.2
72.9
72.3
71.8
69.1
67.0
71.8
64.2
11.9
3.7
2.3
74.3
70.5
70.6
72.4
70.1
72.0
58.8
71.7
67.2
73.0
71.8
63.2
71.7
63.1
8.9
14.5
2.5
9.6
5.1
1.3
56.7
8.1
−14.8
−126.7
9.9
83.3
7.0
101.5
61.3
99.3
102.5
66.5
99.2
65.9
73.4
49.0
106.7
66.1
101.1
72.6
67.3
−6.6
−67.1
−26.8
−11.6
−60.8
−1.70
−10.4
25.0
0.7
−1.5
−74.4
−6.5
92.5
2.2
−7.9
16.0
−13.0
8.9
13.1
7.0
3.2
−16.5
8.3
−16.2
60.5
−94.4
Table 4 Calculated energy (in kcal mol−1) and “φ”/”” (in °) values for all of the conformers of Ac–(D–Oxac)4–OBn 12 within 2 kcal mol−1 in chloroform
Conformer entry
Energy/kcal mol−1
“φ1”
“1”
“φ2”
“2”
“φ3”
“3”
“φ4”
“4”
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
0.00
0.28
0.51
0.78
0.80
0.94
1.37
1.38
1.44
1.54
1.59
1.65
1.77
1.83
1.86
1.93
1.94
72.3
59.7
72.4
73.7
72.5
68.4
73.7
90.3
75.4
69.0
77.9
90.6
89.6
72.5
72.1
59.2
68.5
3.8
−20.4
4.5
7.6
4.9
72.5
75.6
70.1
55.4
71.7
70.8
56.5
50.4
55.1
79.8
63.0
50.5
50.3
72.0
72.2
72.1
58.9
11.7
−162.9
4.1
13.0
4.4
−6.8
9.5
76.0
45.5
71.7
74.8
71.8
68.8
80.0
70.4
79.5
74.1
58.9
72.7
73.1
72.0
44.1
72.1
75.7
6.7
102.0
72.7
99.0
97.0
74.2
99.6
102.5
97.4
101.6
53.6
67.4
102.1
102.1
74.2
104.5
102.7
85.4
−8.0
22.5
−27.3
−19.8
21.6
−10.7
−1.1
−3.6
5.0
91.2
11.0
0.5
8.3
9.9
54.5
7.1
7.2
2.2
8.8
−9.6
−12.2
−32.2
−4.9
−157.2
10.0
−22.3
5.0
−157.7
−159.5
4.6
4.9
−112.7
−3.9
−8.4
9.8
98.3
−131
−10.5
−7.8
4.9
9.8
6.9
19.7
21.9
−10.3
−12.4
−17.7
21.5
−6.3
−6.1
5.5
48.0
3.2
−7.7
102.0
sequently only those lying below 15 kJ mol−1 (about 3.6 kcal mol−1)
were fully analysed.
(chloroform) this stabilization is missing, so that the molecules can
assume both helical and irregularly geometries. The most stable
helical conformation in water has average “” and “φ” torsion
angles 72.6 °, 9.6 ° and 3 D–Oxac residue per turn. The helical
pitch (axial translation per helical turn) is 9.12 Å. This result is
good agreement with the data reported for -proline helices14 and
for poly(Pro)n II helices,15 which both have 3.0 residues per turn.
Fig. 4 shows a superimposition of the six most stable confor-
mations for the D–Oxac tetramer in water and in chloroform,
respectively.
We obtained different results, upon switching the analysis from
structure-supporting solvents (e. g. chloroform) to competitive
solvents (e. g. water). Nevertheless, all of the conformations, both
in water and in chloroform, show an anti orientation for the two
carbonyl groups of each imide moiety. This result is in agreement
with the variations of chemical shifts observed for Ac–(D–Oxac)n–
OBn (n = 2–4) reported in Tables 1 and 2. A similar effect was also
noticed for the L–Oxd4 and pyroglutamic acids5 homo-oligomers.
To describe in detail the results of our computations, we defined
“φ” and “” torsion angles, considering the following “virtual”
bonds for each residue: “φ” =
(Fig. 3).
and “” =
Fig. 3 The “” and “φ” “virtual” torsion angles (in red) used in this work
to describe the computed preferred conformations of the D–Oxac units.
In water there are 14 calculated conformers within 2 kcal mol−1
of the minimum energy conformer that was located at 0 kcal mol−1
(Table 3) versus 17 within 2 kcal mol−1 in chloroform (Table 4).
If we exclude the irrelevant C-terminal D–Oxac ester residue,
the main difference between the two solvents is that in water the
six most stable conformations are regular helices, whereas in
chloroform the second, the fourth and sixth conformations are
irregularly folded. This different behaviour is not unexpected as
it can be ascribed to a competitive effect induced by water which
stabilizes the helical forms where all of the polar carbonyl groups
are accessible to solvation. On the contrary, in a non-polar solvent
Fig. 4 Superposition of the six most stable conformations for Ac–(D–
Oxac)4–OBn in water (left) and in chloroform (right). The conformers
were superimposed with “RMS Fit”, which allows to overlay two or more
molecules by minimizing the distance between corresponding atoms in the
two target molecules.
In order to asses the stability of the extended lowest energy
conformer in water in a longer foldamer, a detailed conformational
analysis was conducted on Ac–(D–Oxac)8–OMe containing eight
units by using the same computational protocol described for
Ac–(D–Oxac)4–OBn 12. The results confirmed the existence of
this helix-like structure even in a longer structure. Indeed only two
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 1 8 1 – 2 1 8 7
2 1 8 3

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Table 5 Calculated energy (in kcal mol−1) and “φ”/”” (in °) values for all of the conformers of Ac–(D–Oxac)8–OBn within 6 kcal mol−1 in water. For clarity
only the minima, maxima and average values are reported
Conformer entry
Energy/kcal mol−1
min “φ”
max “φ”
ave “φ”
min “”
max “”
ave “”
1
2
0.00
4.84
68.0
67.9
72.7
72.0
70.5
70.3
1.4
3.4
8.1
10.2
4.7
6.3
1
The H and 13C chemical shifts in water obtained by means of
stable conformers were found within 6 kcal mol−1 with a geometry in
accordance with what found forAc–(D–Oxac)4–OBn 12 (Table 5 and
Fig. 5). The most stable helical conformation in water has average
“φ” and “” torsion angles 70.5°, 4.7° and three D–Oxac residues
per turn. The helical pitch (axial translation per helical turn) is 8.95 Å.
This result is in agreement with the data reported for 12 in water.
DFT calculations have been compared to those observed in CD3OD
solution (a polar protic solvent similar to water).18 The results are
shown in Table 6, where the H and 13C chemical shifts of the
1
atoms in the ,  and  positions of rings A, B, C, and D have been
compared. NOESY1D experiments (mixing time = 1.0 s) enabled
us to assign all of the protons belonging to the same D–Oxac
unit. Moreover, by means of HSQC experiments, we were able
to assign the signals of all of the carbon atoms. A comparison of
the calculated and measured chemical shifts indicated that in most
cases a good agreement was obtained. In particular, by comparison
of the 1H chemical shifts, the experimental data are in general quite
close to the simulated values, except for a 0.3–0.5 ppm shift to
higher field consistently seen. A particularly good agreement was
also obtained with the measured and calculated values for the 13C
signals, where the difference between the calculated and measured
values is not larger than ± 2 ppm.
Conclusions
A total synthesis and a conformational analysis of the homo-
oligomers of (4R)-(2-oxo-1,3-oxazolidin-4-yl)-acetic acid
(D–Oxac) to the tetramer level has been described. D–Oxac is a
building block which contains both an oxazolidon-2-one and a
-amino acid group. Based on these characteristics we designed
a new type of conformationally constrained -pseudopeptide
foldamers. The synthesis was carried out in the liquid phase in good
yield and the 3D structure of the oligomers was analysed by NMR.
Furthermore, an extensive, unconstrained conformational analysis
was performed with a Monte Carlo search on Ac–(D–Oxac)4–
OBn, both in water and in chloroform to the octamer level. The
conformational analysis clearly showed that this molecule fold in an
ordered helix in competitive solvents such as water. This outcome
Fig. 5 Superposition of the two most stable conformations for Ac–(D–
Oxac)8–OMe in water.
As in water the six preferred conformations are very similar and
regular helices and since the water environment is of major impor-
tance in biological systems, the lowest energy conformation in water
was used as the starting structure for high level DFT calculations
(Fig. 6) which enabled us also to simulate the 1H16 and 13C NMR17
chemical shift () values for the B3LYP/6-31G* optimized structure
of Ac–(D–Oxac)4–OBn (12). On the other hand, a comparison of the
calculated and measured values of 1H and 13C NMR chemical shifts
in chloroform is not significant, because in this case the calculated
conformation is only one out of a complex mixture of conformations,
which have similar energies and are in a fast equilibrium. On the
contrary, the 1H NMR data will not describes a single conformation,
but an average over all the accessible conformations.
1
was further validated by DFT H and 13C NMR simulations that
furnished chemical shifts which were successfully compared with
the experimental values. Since the water environment is of major
importance in biological systems, the molecules described in this
paper are good candidates for biological application.
Experimental
Synthesis and characterization
Materials and reagents were of the highest commercially available
grade and were used without further purification. Reaction were
monitored by thin-layer chromatography using Merck 60 F254
silica gel covered plastic plates. Compounds were visualized by
use of UV light and ceric ammonium molybdate. Flash chromato-
graphy was performed using a Merck a 60 silica gel stationary
1
phase. H and 13C NMR spectra were recorded on a Varian Inova
300, a Varian Mercury 400 or a Varian Inova 600 spectrometer.
Chemical shifts are reported in  values relative to the solvent peak
of CHCl3, set at 7.27 ppm. The experimental chemical shifts were
assigned by means of gCOSY experiments. Infrared absorption
spectra were recorded with a Nicolet 210 FT-IR absorption spectro-
meter. Melting points were determined in open capillaries and are
uncorrected. Microwave-assisted reactions were performed in a
Prolabo Synthewave 402 apparatus ( = 33 MHz, Pmax = 300 W).
Flash chromatography was performed with Merck 60 silica gel
(230–400 mesh).
Fig. 6 (a) Side view of the DFT optimized structure for the preferred
conformer of tetramer (12) in water. (b) Top view. We chose the space
filling model display to show the symmetrical disposition of the oxazolidin-
2-ones rings.
(5-Oxo-tetrahydrofuran-3-yl)-carbamic acid benzyl ester
(1). A mixture of Z–L–Asp–OH (10 mmol, 2.68 g) and Ac2O
(30 mmol, 2.84 mL) was irradiated with microwaves at 70%
2 1 8 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 1 8 1 – 2 1 8 7

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Table 6 Comparison of the experimental (left) and calculated (right) chemical shifts for the homo-oligomer 12
Position
1H
1H
13C



power for 1 min, then the mixture was concentrated. The Z–L–Asp
internal anhydride, crystallized from ethyl acetate, was obtained
pure in 95% yield (2.37 g),19 and was immediately reduced to the
corresponding lactone. A solution of this anhydride (9.5 mmol,
2.37 g) in THF (20 mL) was added dropwise to a suspension of
NaBH4 (10.5 mmol, 0.40 g) in THF (15 mL) at 0 °C. Then, the
suspension was stirred for 16 hr at room temperature, followed by
addition of 6N aqueous HCl to pH 2. THF was evaporated under
reduced pressure, and water (50 mL) was added to the residue. The
mixture was extracted with diethyl ether (4 × 50 mL) and compound
(1) was obtained pure after flash chromatography (cyclohexane/
ethyl acetate 1:1 as eluant) in 80% yield (1.79 g). The yield can
vary, because the lactone (1) can partially or totally be recovered as
the corresponding -hydroxy acid. This side reaction does not affect
the yield of H–D–Oxac–OBn, as both (1) and the corresponding
hydroxy acid are good starting materials for the following reaction.
M.p. = 74 °C; []D − 18.6 (c 1, DCM); IR (film):  = 3309, 1780,
1685 cm−1; 1H-NMR (CDCl3):  = 2.45 (dd, 1 H, J = 2.8, 18.0 Hz),
2.80 (dd, 1 H, J = 7.6, 18.0 Hz), 4.12–4.24 (m, 1 H), 4.36–4.55 (m,
2 H), 5.09 (m, 2 H), 5.44 (bs, 1 H), 7.27–7.32 (m, 5H, Ph); 13C-NMR
(CDCl3):  = 31.8, 35.1, 67.5, 73.8, 128.5, 128.6, 128.9, 136.1,
156.0, 175.3. Elemental analysis for C12H13NO4 (235.2): calcd. C
61.27, H 5.57, N5.95; found C 61.23, H 5.61, N 5.99.
bromide (10 mmol, 1.19 mL), and the mixture was stirred for 24 h.
Then, ethyl acetate was added (50 mL) and the organic layer was
washed with 1N HCl (3 × 20 mL), dried over sodium sulfate, and
concentrated. The product 2 was obtained pure after flash chromato-
graphy (cyclohexane/ethyl acetate 1:1 as eluant) in 60% yield
(3.81 g). mp = 82–83 °C; []D = −32.5 (c 1.0, CH2Cl2); IR (CH2Cl2):
 3240, 1731, 1706 cm−1; 1H NMR (CDCl3, 200 MHz):  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),
5.96 (bs, 1 H, NH), 7.37 (s, 5 H, Ph); 13C-NMR (CDCl3, 200 MHz)
 39.7, 49.0, 67.2, 69.5, 128.5, 128.7, 128.8, 135.2, 159.0, 170.4.
Elemental analysis for C12H13NO4 (235.24): calcd. C 61.27, H 5.57,
N 5.95; found C 61.30, H 5.61, N 5.98.
Ac–D–Oxac–OBn (3). A solution of acetyl chloride (5.5 mmol,
0.40 mL) in DMF (0.5 mL) was added dropwise to a stirred
solution of oxazolidin-2-one (2) (5 mmol, 1.18 g), DIEA (15 mmol,
0.6 mL) and DMAP (2.5 mmol, 0.31 g) in dry DMF (3 mL) The
mixture was stirred for 24 h under nitrogen at room temperature,
then was diluted with ethyl acetate (50 mL), washed with 1 M
aqueous HCl (3 × 30 mL) and 5% aqueous NaHCO3 (1 × 30 mL),
dried over sodium sulfate, and concentrated in vacuo. The fully
protected oxazolidin-2-one (3) was obtained pure in 95% yield
(0.32 g) as an oil after silica gel chromatography (cyclohexane/ethyl
acetate 8:2 as eluant). []D = +126.2 (c 1.2, CH2Cl2); IR (film): 
1779, 1733, 1699 cm−1; 1H NMR (CDCl3, 300 MHz):  2.51 (s, 3 H,
COCH3), 2.70 (dd, 1 H, J = 9.3, 16.5 Hz, CHHCO), 3.14 (dd, 1 H,
J = 3.0, 16.5 Hz, CHHCO), 4.21 (dd, 1 H, J = 3.3, 9.2 Hz, CHHO),
4.52 (t, 1 H, J = 9.2 Hz, CHHO), 4.70–4.78 (m, 1 H, CHN), 5.15
H–D–Oxac–OBn (2). Solid caesium carbonate (27 mmol, 3.06 g)
was added to a stirred solution of 1 (9 mmol, 2.12 g) in acetone
(5 mL) and water (15 mL). The mixture was refluxed for 3 h, then
water and acetone were removed under reduced pressure and the
resulting H–D–Oxac–O− caesium salt was directly transformed into
its benzyl ester. DMF (3 mL) was added to the residue and benzyl
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 1 8 1 – 2 1 8 7
2 1 8 5

View Article Online
(s, 2 H, OCH2Ph), 7.29–7.41 (s, 5 H, Ph); 13C-NMR (CDCl3,
200 MHz)  23.5, 36.3, 50.4, 66.7, 67.1, 128.1, 128.2, 128.3, 134.9,
153.1, 169.5, 170.0. Elemental analysis for C14H15NO5 (277.27):
calcd. C 60.64, H 5.45, N 5.05; found C 60.61, H 5.50, N 5.08.
Ac–(D–Oxac)2–OPfp (8). For the synthetic procedure from (7)
see above the preparation of Ac–D–Oxac–OPfp (5). Yield: 95%; 1H
NMR (CDCl3, 300 MHz):  2.57 (s, 3 H, COCH3), 3.13 (dd, 1 H,
J = 9.2, 17.2 Hz, CHHCO), 3.23 (dd, 1 H, J = 8.0, 17.6 Hz, CHHCO),
3.51 (dd, 1 H, J = 3.2, 17.2 Hz, CHHCO), 3.67 (dd, 1 H, J = 4.8,
17.6 Hz, CHHCO), 4.11 (dd, 1 H, J = 5.8, 9.0 Hz, CHHO), 4.31 (dd,
1 H, J = 3.6, 9.4 Hz, CHHO), 4.58 (t, 1 H, J = 9.0 Hz, CHHO), 4.66
(t, 1 H, J = 9.4 Hz, CHHO), 4.80–4.94 (m, 1 H, CHN).
Ac–D–Oxac–OH (4). To a solution of the fully protected
oxazolidin-2-one (3) (4 mmol, 1.11 g) in ethyl acetate (20 mL)
was added 10% palladium on charcoal (0.10 g) and the mixture
was stirred in a Parr apparatus under 3 atm of hydrogen for 1 h.
Then, the catalyst was filtered on a celite pad and the mixture
was concentrated. The carboxylic acid (4) was obtained pure in
quantitative yield (0.74 g) without any further purification.
[]D = +110.6 (c 0.2, acetone); IR (CH2Cl2):  3231, 1779, 1719,
1673 cm−1; 1H NMR (CDCl3, 200 MHz):  2.54 (s, 3 H, COCH3),
2.74 (dd, 1 H, J = 9.6, 17.2 Hz, CHHCO), 3.19 (dd, 1 H, J = 2.6,
17.2 Hz, CHHCO), 4.23 (dd, 1 H, J = 3.4, 9.2 Hz, CHHO), 4.56
(t, 1 H, J = 9.2 Hz, CHHO), 4.69–4.84 (m, 1 H, CHN); 13C-NMR
(acetone d6, 200 MHz)  23.7, 36.4, 51.5, 68.0, 154.2, 170.5, 171.7.
Elemental analysis for C7H9NO5 (187.15): calcd. C 44.92, H 4.85,
N 7.48; found C 44.96, H 4.78, N 7.50.
Ac–(D–Oxac)3–OBn (9). For the synthetic procedure from (2)
and (8) see above the preparation of Ac–(D–Oxac)2–OBn (6). Yield
50%; mp = 186–188 °C; []D = +130.2 (c 1.0, CH2Cl2); IR (nujol):
1
 1772, 1706, 1686 cm−1; H NMR (CDCl3, 400 MHz):  2.52 (s,
3 H, COCH3), 2.74 (dd, 1 H, J = 9.6, 17.2 Hz, CHHCO), 3.10 (dd,
1 H, J = 3.9, 17.0 Hz, CHHCO), 3.27 (dd, 2 H, J = 8.1, 17.7 Hz,
2 × CHHCO), 3.52–3.64 (m, 2 H, 2 × CHHCO), 4.03–4.15 (m, 2 H,
2 × CHHO), 4.25 (dd, 1 H, J = 3.3, 9.3 Hz, CHHO), 4.48–4.62 (m,
3 H, 3 × CHHO), 4.72–4.88 (m, 3 H, 3 × CHN), 5.15 (AB, 2 H,
J = 12.0 Hz, OCH2Ph), 7.28–7.42 (m, 5 H, Ph); 13C-NMR (CDCl3,
300 MHz)  23.7, 36.4, 38.5, 38.6, 50.5, 50.6, 50.8, 67.1, 67.5, 67.8,
68.0, 128.5, 128.6, 128.7, 135.1, 153.1, 169.6, 169.7, 170.0, 170.1,
170.4, 170.5. Elemental analysis for C27H37N3O11 (579.60): calcd. C
55.95, H 6.43, N 7.25; found C 55.91, H 6.46, 7.21.
Ac–D–Oxac–OPfp (5). To a stirred solution of carboxylic acid
(4) (2 mmol, 0.37 g) in dry DMF (1 mL) pyridine (2.2 mmol,
0.17 mL) was added, followed by pentafluorophenyl trifluoro-
acetate (2.5 mmol, 0.52 mL). The reaction was allowed to stir
for 45 min at room temperature, then it was diluted with ethyl
acetate (50 mL), washed with 0.1 M aqueous HCl (2 × 30 mL)
and 5% aqueous NaHCO3 (1 × 30 mL), dried over sodium sulfate,
and concentrated in vacuo. The pentafluorophenyl ester 5 was
obtained in quantitative yield, but it could not be purified by silica
Ac–(D–Oxac)3–OH (10). For the synthetic procedure from (9)
see above the preparation of Ac–D–Oxac–OH (4). Yield: 92%.
mp = 192–195 °C; []D = +187.5 (c 1.0, CH2Cl2); IR (nujol): 
1
3510, 1786, 1733, 1693 cm−1; H NMR (acetone d6, 300 MHz): 
2.41 (s, 3 H, COCH3), 2.87 (dd, 1 H, J = 9.0, 17.1 Hz, CHHCO),
3.06 (dd, 1 H, J = 2.7, 17.1 Hz, CHHCO), 3.30 (dd, 1 H, J = 9.0,
18.0 Hz, 2 × CHHCO), 3.34 (dd, 1 H, J = 9.0, 18.0 Hz, CHHCO),
3.56 (dd, 1 H, J = 3.3, 18.0 Hz, 2 × CHHCO), 3.58 (dd, 2 H, J = 3.3,
18.0 Hz, 2 × CHHCO), 4.19 (dd, 1 H, J = 3.6, 9.0 Hz, CHHO), 4.23
(dd, 1 H, J = 3.9, 9.0 Hz, CHHO), 4.32 (dd, 1 H, J = 4.5, 9.0 Hz,
CHHO), 4.52–4.63 (m, 3 H, 3 × CHHO), 4.70–4.86 (m, 3 H,
3 × CHN); 13C-NMR (acetone d6, 300 MHz)  23.7, 36.5, 38.9,
39.0, 51.5, 51.6, 51.7, 68.3, 68.5, 68.7, 154.4, 154.6, 170.8, 171.2,
171.4, 172.1. Elemental analysis for C21H28N2O8 (489.20): calcd. C
49.08, H 6.38, N 8.58; found C 49.11, H 6.35, N 8.62.
1
gel chromatography. H NMR (CDCl3, 300 MHz):  2.58 (s, 3 H,
COCH3), 3.08 (dd, 1 H, J = 9.3, 17.4 Hz, CHHCO), 3.49 (dd, 1 H,
J = 3.3, 17.4 Hz, CHHCO), 4.28 (dd, 1 H, J = 3.6, 9.3 Hz, CHHO),
4.61 (t, 1 H, J = 9.3 Hz, CHHO), 4.80–4.92 (m, 1 H, CHN).
Ac–(D–Oxac)2–OBn (6). Ac–D–Oxac–OPfp (5) (2 mmol, 0.82 g)
in dry DMF (2 mL) was added in one portion to a stirred solution of
H–D–Oxac–OBn (2) (1.9 mmol, 0.45 g), DIEA(3.8 mmol, 1.11 mL)
and DMAP(0.2 mmol, 24 mg) in dry DMF (3 mL). The reaction was
allowed to stir for 16 h at room temperature, then it was diluted with
ethyl acetate (50 mL), washed with 0.1 M aqueous HCl (2 × 30 mL)
and 5% aqueous NaHCO3 (1 × 30 mL), dried over sodium sulfate
and concentrated in vacuo. The di-oxazolidin-2-one (6) was obtained
pure in 70% yield (0.58 g) as a white solid after silica gel chromato-
graphy (cyclohexane/ethyl acetate 9:1 as eluant). mp = 82–84 °C;
[]D = +108.3 (c 1.0, CH2Cl2); IR (CH2Cl2):  1790, 1734, 1702 cm−1;
1H NMR (CDCl3, 400 MHz):  2.53 (s, 3 H, COCH3), 2.74 (dd, 1 H,
J = 9.6, 17.2 Hz, CHHCO), 3.14 (dd, 1 H, J = 4.0, 17.2 Hz, CHHCO),
3.20 (dd, 1 H, J = 8.8, 17.8 Hz, CHHCO), 3.63 (dd, 1 H, J = 3.6,
17.8 Hz, CHHCO), 4.08 (dd, 1 H, J = 3.6, 9.2 Hz, CHHO), 4.26 (dd,
1 H, J = 4.0, 9.6 Hz, CHHO), 4.55 (t, 1 H, J = 9.2 Hz, CHHO), 4.62
(t, 1 H, J = 9.6 Hz, CHHO), 4.71–4.79 (m, 1 H, CHN), 4.82–4.89 (m,
1 H, CHN), 5.15 (AB, 2 H, J = 12.0 Hz, OCH2Ph), 7.31–7.42 (m,
5 H, Ph); 13C-NMR (CDCl3, 300 MHz)  23.6, 36.3, 38.7, 50.5, 50.7,
67.0, 67.6, 67.8, 128.4, 128.5, 128.6, 135.0, 153.0, 153.3, 169.6,
169.9, 170.5. Elemental analysis for C21H28N2O8 (436.46): calcd. C
57.79, H 6.47, N 6.42; found C 57.76, H 6.51, N 6.45.
Ac–(D–Oxac)3–OPfp (11). For the synthetic procedure from
(10) see above the preparation of Ac–D–Oxac–OPfp (5). Yield:
1
95%; H NMR (CDCl3, 200 MHz):  2.54 (s, 3 H, COCH3), 3.15
(dd, 1 H, J = 8.8, 17.2 Hz, CHHCO), 3. 31 (dd, 1 H, J = 8.2,
17.6 Hz, CHHCO), 3.36 (dd, 1 H, J = 7.8, 17.6 Hz, CHHCO), 3.48
(dd, 1 H, J = 3.4, 17.2 Hz, CHHCO), 3.60 (dd, 1 H, J = 4.8, 17.6 Hz,
2 × CHHCO), 3.63 (dd, 1 H, J = 4.2, 17.6 Hz, 2 × CHHCO), 4.09–
4.21 (m, 2 H, 2 × CHHO), 4.32 (dd, 1 H, J = 3.6, 9.4 Hz, CHHO),
4.51–4.74 (m, 3 H, CHHO), 4.81–4.93 (m, 3 H, 3 × CHN).
Ac–(D–Oxac)4–OBn (12). For the synthetic procedure from
(2) and (11) see above the preparation of Ac–(D–Oxac)2–OBn (5).
Yield 50%. mp = 206–210 °C; []D = +73.3 (c 0.3, CH2Cl2); IR
(CH2Cl2):  1791, 1732, 1699 cm−1; 1H NMR (CDCl3, 300 MHz):
 2.52 (s, 3 H, COCH3), 2.75 (dd, 1 H, J = 9.3, 16.5 Hz, CHHCO),
3.12 (dd, 1 H, J = 3.0, 16.5 Hz, CHHCO), 3.22–3.38 (m, 3 H,
3 × CHHCO), 3.50–3.68 (m, 3 H, 3 × CHHCO), 4.06–4.18 (m,
3 H, 3 × CHHO), 4.25 (dd, 1 H, J = 3.6, 9.3 Hz, CHHO), 4.51–4.63
(m, 4 H, 3 × CHHO), 4.72–4.90 (m, 4 H, 4 × CHN), 5.15 (AB, 2 H,
J = 12.0 Hz, OCH2Ph), 7.30–7.42 (m, 5 H, Ph); 13C-NMR (CDCl3,
300 MHz)  23.7, 36.4, 38.4, 38.6, 38.7, 50.6, 50.7, 50.8, 50.9, 67.1,
67.2, 67.8, 67.9, 68.1, 128.5, 128.6, 128.7, 135.1, 153.1, 153.4,
169.5, 169.6, 169.7, 169.8, 170.0, 170.2, 170.5. Elemental analysis
for C33H46N4O14 (722.74): calcd. C 54.84, H 6.42, N 7.75; found C
54.80, H 6.47, N 7.70.
Ac–(D–Oxac)2–OH (7). For the synthetic procedure from (6)
see above the preparation of Ac–D–Oxac–OH (4). Yield: 92%;
mp = 179–181 °C (dec.); []D = +161.3 (c 1.0, acetone); IR (nujol):
1
 3297, 1772, 1752, 1726, 1706, 1686 cm−1; H NMR (CDCl3,
400 MHz):  2.53 (s, 3 H, COCH3), 2.77 (dd, 1 H, J = 8.8, 16.8 Hz,
CHHCO), 3.08–3.30 (m, 2 H, CHHCO + CHHCO), 3.67 (dd, 1 H,
J = 4.8, 18.4 Hz, CHHCO), 4.09 (dd, 1 H, J = 3.6, 9.2 Hz, CHHO),
4.28 (dd, 1 H, J = 43.6, 9.0 Hz, CHHO), 4.57 (t, 1 H, J = 9.2 Hz,
CHHO), 4.61 (t, 1 H, J = 9.0 Hz, CHHO), 4.68–4.80 (m, 1 H,
CHN), 4.82–4.93 (m, 1 H, CHN); 13C-NMR (acetone d6, 300 MHz)
 23.7, 36.5, 39.0, 51.5, 51.7, 68.3, 68.5, 154.4, 170.8, 171.2, 172.1.
Elemental analysis for C14H22N2O8 (346.33): calcd. C 48.55, H 6.40,
N 8.09; found C 48.52, H 6.43, N 8.12.
Ac–(D–Oxac)4–OH (13). For the synthetic procedure from (12)
see above the preparation of Ac–D–Oxac–OH (4). Yield: 92%.
mp = 149–150 °C (dec.); []D = +117.2 (c 0.1, acetone); IR (nujol):
 3610, 3523, 1747, 1739, 1735, 1730, 1727, 1687, 1679 cm−1; 1H
NMR (acetone d6, 400 MHz):  2.40 (s, 3 H, COCH3), 2.81–2.91
2 1 8 6
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 1 8 1 – 2 1 8 7

View Article Online
3 B. R. Huck, J. D. Fisk, I. A. Guzei, H. A. Carlson and S. H. Gellman, J.
Am. Chem. Soc., 2003, 125, 9035.
4 (a) S. Lucarini and C. Tomasini, J. Org. Chem., 2001, 66, 727;
(b) C. Tomasini, V. Trigari, S. Lucarini, F. Bernardi, M. Garavelli,
C. Peggion, F. Formaggio and C. Toniolo, Eur. J. Org. Chem., 2003,
259.
5 F. Bernardi, M. Garavelli, M. Scatizzi, C. Tomasini, V. Trigari,
M. Crisma, F. Formaggio, C. Peggion and C. Toniolo, Chem. Eur. J.,
2002, 8, 2516.
6 (a) D. Seebach and J. L. Matthews, J. Chem Soc. Chem. Commun., 1997,
2015; (b) W. F. DeGrado, J. P. Schneider and Y. Hamuro, J. Peptide
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Chem. Rev., 2001, 101, 3219.
(m, 1 H, CHHCO), 3.01–3.08 (m, 1 H, CHHCO), 3.20–3.41 (m,
3 H, 3 × CHHCO), 3.51–3.63 (m, 3 H, CHHCO), 4.10–4.23 (m,
3 H, 3 × CHHO), 4.25–4.36 (m, 1 H, CHHO), 4.53–4.63 (m,
4 H, 4 × CHHO), 4.70–4.78 (m, 1 H, CHN), 4.79–4.85 (m, 3 H,
3 × CHN); 13C-NMR (acetone d6, 400 MHz)  23.1, 35.9, 38.2, 38.3,
38.4, 50.8, 50.9, 51.0, 51.1, 67.6, 67.7, 67.9, 68.0, 153.7, 153.9,
154.0, 170.1, 170.2, 170.6, 170.7, 170.8, 171.0, 171.5. Elemental
analysis for C26H40N4O14 (436.46): calcd. C 49.36, H 6.37, N 8.86;
found C 49.33, H 6.38, N 8.85.
Computational methods
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All calculations were carried out on SGI IRIX 6.5 workstations.
Molecular mechanics calculations were performed using the
implementation of OPLS force field (OPLS*)12 within the
framework of Macromodel version 5.5.20 The solvent effect was
included by the implicit chloroform GB/SA solvation model of
Still et al.13 The torsional space of each molecule was randomly
varied with the usage-directed Monte Carlo conformational search
of Chang, Guida, and Still.11 For each search, at least 1000 starting
structures for each variable torsion angle were generated and
minimized until the gradient was less than 0.05 kJ Å−1 mol−1. The
cyclic moieties containing the urethane bonds were also included
into the search. Duplicate conformations and those with an energy in
excess of 25 kJ mol−1 above the global minimum were discarded.
All DFT calculations (i.e., geometry optimizations and chemical
shift simulations) were carried out using the standard tools available
in the Gaussian 98 package,21 with the DFT/B3LYP functional (i.e.,
the Becke’s three parameter hybrid functional with the Lee-Yang-
Parr correlation functional)22 and the 6–31G(d) basis set. This
functional and basis set have been shown to properly describe both
standard hydrogen bonds,23 as well as non-classical, weak hydrogen
bonds (such as C–HOC interactions),24 and to provide reliable
results for the chemical shifts.16,17 It should be noted that computed
data do not directly yield the chemical shift value, but only a value
for the isotropic magnetic tensor. The chemical shift values are
obtained from the following equations:
14 L. M. Sandvoss and H. A. Carlson, J. Am. Chem. Soc., 2003, 125,
15855.
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(b) R. Z. Kramer, L. Vitagliano, J. Bella, R. Berisio, L. Mozzarella,
B. Brodsky, A. Zagari and H. M. Barman, J. Mol. Biol., 1998, 280, 623;
(c) E. Beausoleil and W. D. Lubell, Biopolymers, 2000, 53, 249.
16 (a) K. Wolinski, J. F. Hilton and P. Pulay, J. Am. Chem. Soc., 1990, 112,
8251; (b) J. L. Dodds, R. McWeeny and A. J. Sadlej, Mol. Phys., 1980,
41, 1419; (c) R. Ditchfield, Mol. Phys., 1974, 27, 789; (d) R. McWeeny,
Phys. Rev., 1962, 126, 1028; (e) F. London, J. Phys. Radium, 1937, 8,
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H = 32.18 − H
c = 189.73 − c
where 32.18 and 189.73 are the calculated isotropic magnetic ten-
sors for the protons and carbons in tetramethylsilane, respectively,
and H and c are the calculated isotropic magnetic tensors for the
investigated protons and carbons.
18 The experimental chemical shifts were measured in CD3OD at 600 MHz
and were assigned by means of NOESY1D and HSQC experiments.
19 T. Munegumi, Y.-Q. Meng and K. Harada, Chem. Lett., 1989, 62, 2748.
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Acknowledgements
21 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman, V. G. Zakrzewski, J. A. Montgomery Jr., R. E.
Stratmann, J. C. Burant, S. Dapprich, J. M. Millan, A. D. Daniels,
K. N. Kudin, M. C. Strain, O. Farkas, J. Tomasi, V. Barone, M. Cossi,
R. Cammi, B. Mennucci, C. Pomelli, C. Adamo, S. Clifford,
J. Ochterski, G. A. Patersson, P. Y. Ayala, Q. Cui, K. Morokuma, D. K.
Malik, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. Cioslowski,
J. V. Ortiz, A. G. Baboul, B. B. Stefanov, G. Liu, A. Liashenko,
P. Piskorz, I. Komaromi, R. Gomperts, R. L. Martin, D. J. Fox, T. Keith,
M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe,
P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, J. L. Andres,
C. Gonzales, M. Head-Gordon, E. S. Replogle, J. Pople, Gaussian 98,
Revision A.9, Gaussian Inc., Pittsburgh, PA, 1998.
The authors are grateful to prof. Claudio Toniolo (Department of
Chemistry, University of Padova) for stimulating discussions. C. T.
and G. L. thank MURST Cofin 2002 (“Sintesi di peptidi ciclici o
lineari contenenti amminoacidi inusuali analoghi di arginina, glicina
o acido aspartico (RGD) come nuovi inbitori di integrine”), FIRB
2001 (“Eterocicli azotati come potenziali inbitori enzimatici”) and
60% (Ricerca Fondamentale Orientata), and the University of
Bologna (funds for selected topics “Sintesi e Caratterizzazione di
Biomolecole per la Salute Umana”) for financial support.
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