Synthesis and secondary structure of alternate α,β-hybrid peptides containing oxazolidin-2-one moieties

Article abstract of DOI:10.1002/ejoc.200700134

The synthesis and conformational analysis of a novel class of foldamers containing (S)-β³-homophenylglycine [(S)-β³- hPhg] and D-4-carboxy-oxazolidin-2-one (D-Oxd) residues in alternate order is reported. The experimental conformatio

Full text of DOI:10.1002/ejoc.200700134

FULL PAPER
DOI: 10.1002/ejoc.200700134
Synthesis and Secondary Structure of Alternate α,β-Hybrid Peptides
Containing Oxazolidin-2-one Moieties
Gaetano Angelici,[a] Gianlugi Luppi,[a] Bernard Kaptein,[b] Quirinus B. Broxterman,[b]
Hans-Jörg Hofmann,[c] and Claudia Tomasini*[a]
Keywords: Hybrid peptides / Foldamers / Amino acids / Ab initio calculations
The synthesis and conformational analysis of a novel class of
gest a helix with 11-membered hydrogen-bonded rings as
the preferred secondary structure type. The few formal helix
alternatives can be excluded in particular by steric effects of
the oxazolidin-2-one rings. The novel structures enrich the
field of peptidic foldamers and might be useful in the mim-
icry of native peptides.
foldamers containing (S)-β3-homophenylglycine [(S)-β3-
hPhg] and D-4-carboxy-oxazolidin-2-one (D-Oxd) residues in
alternate order is reported. The experimental conformational
analysis performed in solution by IR, 1H NMR, and CD spec-
troscopy unambiguously proved that these oligomers fold
into ordered structures with increasing sequence length.
Theoretical calculations employing ab initio MO theory sug-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Here, we report the synthesis of novel foldamers with the
general formula Boc-[(S)-β3-hPhg--Oxd]n-OR (Figure 1).
(S)-β3-hPhg is the abbreviation for (S)-β3-homophenylgly-
cine[6] and -Oxd is that for trans-(4R,5S) 4-carboxy-5-
methyloxazolidin-2-one.[7] Thus, the periodic foldamer unit
consists of a β-amino acid constituent followed by the pro-
line mimetic -Oxd as an α-amino acid. We expect that
these molecules have several constraints due to the presence
of the cyclic -Oxd moiety that enforces the peptide bond,
actually an imide bond, exclusively into the trans conforma-
tion owing to the presence of the endocyclic carbonyl
group. The possibility of intramolecular hydrogen bonds
would favor secondary structure formation as found in the
above-mentioned regular α,β-hybrid peptides.
Introduction
The synthesis of peptide-like oligomers that fold into
definite secondary structures is a great challenge for the
community of synthetic organic chemists. Such molecules
have been defined as foldamers by Gellman.[1] In the last
decade, several groups succeeded in the preparation of
homooligomers or heterooligomers of homologous amino
acids, mainly β-amino acids, with defined secondary struc-
tures.[2]
Recently, several examples of foldamers were reported
containing a mixture of α- and β-, α- and γ-, or β- and γ-
amino acids in alternating order.[3] Besides helical structures
with hydrogen bonds pointing only in one direction, either
backward or forward along the sequence, also mixed helices
(β-helices) with hydrogen bonds alternately changing in the
forward and backward directions were found in these regu-
lar hybrid peptides.[3,4] In several cases, an increased resis-
tance of the pseudopeptides against proteases was indicated
in comparison to their native counterparts. Moreover, even
biological activity of such peptidomimetics was found.[5] All
these results make peptidic foldamers consisting of homolo-
gous amino acids highly attractive for several purposes and
stimulate the search for novel foldamer classes.
Figure 1. General formula of the oligomers.
[a] Dipartimento di Chimica “G. Ciamician” – Alma Mater Stu-
diorum Università di Bologna
Via Selmi 2, 40126 Bologna, Italy
Results and Discussion
Fax: +39-05102099456
E-mail: claudia.tomasini@unibo.it
[b] DSM Research, Pharmaceutical Products – Advanced Synthe-
sis & Catalysis,
Synthesis
Oligomers up to the 12-mer level (n = 6 in Figure 1) were
synthesized in the liquid phase (Scheme 1). At first, the di-
mer Boc-(S)-β3-hPhg--Oxd-OBn (2) was prepared by the
addition of Boc-(S)-β3-hPhg-OH to -Oxd-OBn (1) in the
P. O. Box 18, 6160 MD Geleen, The Netherlands
[c] Institut für Biochemie, Universität Leipzig,
Brüderstraße 34, 04103 Leipzig, Germany
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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C. Tomasini et al.
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presence of N-[(1H-benzotriazol-yl)(dimethylamino)methyl- tra (NH stretching region) for all the synthesized com-
ene]-N-methylmethaneiminium hexafluorophosphate N-ox- pounds. They help to detect nonhydrogen-bonded amide
ide (HBTU) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) NH bands (above 3400 cm–1) and hydrogen-bonded amide
in acetonitrile in excellent yield. Then, C-deprotected dimer proton bands (below 3400 cm–1). These preliminary results
3 and N-deprotected dimer 4 were obtained by selective de- suggest that the longer oligomers of this series form strong
protection of the C-terminal benzyl ester with H2 in meth- hydrogen bonds, as was observed for the oligomers of the
anol in the presence of Pd/C (5%) and of the N-terminal -Ala--Oxd series.[9]
Boc moiety with anhydrous trifluoracetic acid (TFA) in
dichloromethane, respectively. Treatment of 4 with a weak
base (NaHCO3) provided the corresponding free amine,
which proved to be very unstable. Therefore, 4 was coupled
as such by utilizing an excess of triethylamine (TEA).
Figure 2. FT-IR absorption spectra in the NH stretching region for
3 m samples of oligomers 2, 5, 7, 9, 11, and 13 in pure CH2Cl2
at room temperature.
Monomer 2 has only one absorption band at 3439 cm–1
due to a nonhydrogen-bonded amide NH. Obviously, the
Scheme 1. (i) HBTU (1 equiv.), DBU (1 equiv.), dry CH3CN, room
sequence length is not sufficient for an effective hydrogen
temp. 40 min; (ii) H2, Pd/C (10%), MeOH, room temp., 16 h; (iii)
bond. Contrary to this, the maximum of the corresponding
TFA (18 equiv.), dry CH2Cl2, room temp., 2 h; (iv) HATU
absorption band shifts slowly towards 3289 cm–1 in hexa-
(1.1 equiv.), Et3N (3 equiv.), dry CH3CN, 40 min, room temp.
mer 13, which thus demonstrates that the NH hydrogens
are now chelated and form possibly an ordered secondary
structure, such as a helix. It is worth mentioning that trimer
Moieties 3 and 4 were coupled with O-(7-azabenzotri-
azol-1-yl)-N,N,NЈ,NЈ-tetramethyluronium hexafluorophos-
phate (HATU) and TEA in dry acetonitrile under an inert
7 shows an absorption band with a broad maximum located
between 3416 and 3344 cm–1. This suggests that even in this
oligomer, an ordered structure is favored, although still in
an equilibrium with nonordered structures.
atmosphere to provide dimer 5 in satisfactory yield. By de-
protection of the carbobenzoxy group with H2 in methanol
in the presence of Pd/C (5%), corresponding acid 6 was
obtained in quantitative yield. The coupling step was re-
peated to get 7 in good yield as well. Repetition of these
two steps finally led to Boc-[(S)-β3-hPhg--Oxd]6-OH (14).
All compounds are stable at room temperature and soluble
in acetonitrile, acetone, methanol, and DMSO.
For further validation of these results, the oligomers were
1
analyzed by H NMR spectroscopy. We have already dem-
onstrated that the formation of nonconventional, weak
CH···O=C intramolecular H-bonds can simply be spotted
by checking the α-proton chemical shift because the car-
bonyl proximity leads to a remarkable deshielding of the
proton chemical shift.[10] This effect was also observed in β-
amino acid derivatives like the homooligomers of (4R)-(2-
Conformational Analysis
Information on the conformation of the described oligo- oxo-1,3-oxazolidin-4-yl)acetic acid (-Oxac).[11]
mers in solution was obtained by FT-IR, 1H NMR spectro-
The same trend can be seen when analyzing the 1H NMR
scopic, and CD techniques in structure-supporting solvents chemical shifts of the methylene hydrogens of the β3-homo-
(dichloromethane, deuteriochloroform, and methanol) as phenylglycine moiety in these compounds. Indeed, these hy-
well as DMSO.
drogens are always more deshielded by about 0.3–0.4 ppm
The FT-IR absorption spectra of benzyl esters 2, 5, 7, 9, in comparison to the chemical shift of Boc–β3-homophen-
11, and 13 were obtained from 3 m solutions in dichloro- ylglycine,[12] which thus shows that they suffer the effect of
methane. At this concentration, self-aggregation is usually an oxazolidin-2-one carbonyl group in the vicinity of the
unimportant.[8] Figure 2 shows the FT-IR absorption spec- CαH proton in such a way that the imide–CO–N bond ex-
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Alternate α,β-Hybrid Peptides Containing Oxazolidin-2-one Moieties
FULL PAPER
ternal to the ring system is forced into the trans conforma-
tion. A strictly comparable trend was observed for the C-
deprotected series, which is not shown here.
Furthermore, the occurrence of intramolecular
C=O···H–N hydrogen bonds in trimer 7 has been detected
by an investigation of the [D6]DMSO dependence of the
NH proton chemical shifts (Figure 3).[13] DMSO is a strong
hydrogen-bond acceptor and, if it is bound to a free NH
proton, a considerable downfield shift of the proton signal
can be expected.
Figure 3. Variation of the NH proton chemical shifts [ppm] of 7 as
a function of increasing percentages of [D6]DMSO added to the
CDCl3 solution (v/v) (concentration: 1 m).
Figure 4. Variation of NH proton chemical shifts [ppm] of the five
amide protons and the Boc-NH proton of 13 as a function of the
temperature for 3 m samples measured in [D6]DMSO: (a) amide
NH; (b) Boc-NH.
The results of this titration are in good agreement with
the results obtained by FTIR spectroscopy. The NH pro-
tons of Boc-(L-Ala--Oxd)3-OBn (7) are somehow sensitive
to DMSO, which confirms the tendency of 7 to form a hy-
drogen bond driven secondary structure. However, this sec-
Whereas the five recorded amide protons have small tem-
ondary structure cannot yet be well established in this short perature coefficients consistent with those for hydrogen-
sequence. Unfortunately, it was impossible to perform the bonded NH protons, the Boc-NH has a larger temperature
titration of longer oligomers 11 and 13 as a result of their coefficient, which suggests that this proton is not involved
low solubility in CDCl3. Only in a mixture of CDCl3 and in a hydrogen bond. This might be caused by its position
[D6]DMSO (minimum 5%), could 1H NMR spectra be ob- at the beginning of the chain. Finally, NOESY experiments
tained, but with a very poor resolution. We could only re- were recorded on the same solution of 13 to obtain more
1
cord H NMR spectra exhibiting complex signals that can structural information. Figure 5a and Figure 5b show cross
be attributed to the NH hydrogens at 8.5–8.8 ppm. On ad- peaks between the NH amide hydrogens (8.50–9.00 ppm)
dition of further portions of [D6]DMSO, this complex and the NH carbamate hydrogen. Giving as assumption
pattern is shifted by less than 0.3 ppm downfield, which that the NHǞNH cross peaks may be ascribed to
suggests that these signals belong to chelated hydrogens. NiHǞNi+1H interaction, we could assign the chemical shift
For a better evaluation of the presence of N–H···O=C hy- to the NH hydrogens. The presence of these cross peaks
1
drogen bonds, we recorded some H NMR spectra of 13 in indicate the formation of a helix.[16] Furthermore, interest-
[D6]DMSO (3 m solution) at different temperatures (Fig- ing NHǞHc, NHǞHd, and NHǞMe cross peaks can be
ure 4). In the solvent CDCl3, small temperature coefficients detected (Figure 5c and Figure 5d; for signal assignment
of Յ 3 ppb/K indicate the presence of hydrogen-bonded Figure 6) but unfortunately these signals overlap.
amide protons,[14] whereas protons that participate in an
Some support of the formation of an ordered secondary
equilibrium between hydrogen-bonded and nonhydrogen- structure in the longer oligomers comes from the CD spec-
bonded states show larger temperature coefficients. In [D6]- tra of free acids 3, 6, 8, 10, 12, and 14 in MeOH solution
DMSO, the criterion for the temperature coefficients is a (Figure 7). Although this technique is intrinsically a low
bit higher. Thus, the values for hydrogen-bonded amide resolution method,[17] it can provide useful information on
protons are 4 ppb/K or smaller.[15]
the presence of secondary structures.[18]
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C. Tomasini et al.
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Figure 5. Significant NOE enhancements of 13 obtained by performing NOESY experiments on a 3 m solution in [D6]DMSO utilizing
a mixing time of 0.400 s at 25 °C: (a) cross peaks between the NHǞNH amide hydrogens (NH amide: 8.80–9.10 ppm); (b) cross peak
between NH amide and NH carbamate hydrogen (NH carbamate: about 7.40 ppm); (c) NHǞHc and NHǞHd cross peaks (Hc and Hd:
4.20–4.50 ppm); (d) NHǞMe cross peaks (Me: 1.20–1.45 ppm).
Figure 6. Results for the NOESY experiments on 13 shown in Figure 5.
Deeper inspection of the spectra shows a great difference
To get more insight into the nature of the hydrogen-
between the normalized per-residue spectra of 3, 12, and bonded secondary structure indicated by the experimental
14. The spectrum of 3 exhibits a minimum at 193 nm and a investigations, quantum chemical calculations were per-
maximum at 202 nm. The minimum slowly moves towards formed on oligomers 7 and 13 by employing ab initio MO
196 nm in the longer oligomers with increasing intensity. theory at the HF/6-31G* level (for computational details,
The maximum at 202 nm gradually disappears and is re- see Experimental Section). This approximation level was
placed by a shoulder at 202–206 nm. The CD spectrum of successfully used in the prediction of the conformation of
14 is even different with a minimum at 197 nm having a peptide foldamers in numerous cases.[4a–4c,4f–4h,20] Thus, it
much lower intensity and a new maximum at 220 nm. This was possible to predict all helix types that can be expected
variation suggests the formation of an ordered structure, in oligomers of regular α,β-hybrid peptides.[4h] A look at
although the CD spectra are not able to determine the ac- this catalogue of basic helices shows that several of them
tual nature of this structure. Recently, CD spectra of α,β- can a priori be excluded in our case as a result of the torsion
hybrid peptides were reported,[3b,3h,3i] but a clear corre- angle φ of the α-amino acid constituent -Oxd kept fixed
lation between structured helices and CD spectra, as it is at values of about 60°. Thus, only three helix types have to
known for native helices, could not be established.[19]
be taken into consideration. Two helices are with backward
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Alternate α,β-Hybrid Peptides Containing Oxazolidin-2-one Moieties
FULL PAPER
Figure 7. Normalized per-residue CD spectra of 3, 6, 8, 10, 12, and
14 (1 m concentration in MeOH solution).
directions of the hydrogen bonds along the sequence. In the
one, H11, 11-membered hydrogen-bonded cycles are
formed, in the other, H14/15, 14- and 15-membered hydro-
gen-bonded rings alternate, but keep their backward hydro-
gen bond directions. The third helix type, H11/9, is a β- or
mixed helix with the hydrogen bond directions alternating
in the forward and backward directions to form 11- and 9-
membered hydrogen-bonded pseudocycles. These three he-
lix types of alternate α,β-hybrid peptides that were pre-
dicted by theory and also experimentally confirmed,[3]
served as starting points for calculations on trimers (n =
3) and hexamers (n = 6) of our oligomers (Figure 1). In
comparison to α,β-hybrid peptides consisting of ordinary
α- and β-amino acids, our oligomers are only able to form
every second hydrogen bond because of the oxazolidin-2-
one constituent, that is, only every second 11-membered
ring appears in H11, and the 15-membered rings in H14/15
and the 11-membered rings in H11/9 are missing. Thus, the
helices of our oligomers should be less stable than those in
the ordinary α,β-hybrid peptides for a given sequence
length. This could also be the reason for the experimentally
found increasing tendency of secondary structure formation
in the longer sequences. According to the calculations, a
left-handed helix H11 is most stable. The structure is a bit
distorted in the trimer, but rather perfect in the hexamer
(Figure 8). The helix H14/(15) cannot be kept because of ste-
ric effects caused by the oxazolidin-2-one ring. Optimiza-
tion of the H14/(15) starting structure tends to the formation
of 11-membered hydrogen-bonded pseudocycles. A left-
handed mixed helix H(11)/9 with in fact only nine-membered
hydrogen-bonded rings is principally possible (Figure 8).
However, the hexamer H(11)/9 is by 7.6 kcalmol–1 less stable
than the H11 hexamer. Apart from a correct overall shape,
the hydrogen bond lengths are too long. The energy differ-
ence between both helix types is reduced to 2.9 kcalmol–1
in an aqueous environment as shown by the estimation of
the solvation energy on the basis of a polarizable contin-
uum model (total energies of both helices are given in the
Supporting Information; pdb files are available from the au-
thors on request).
Figure 8. Most stable helix types H11 and H(11)/9 in hexamers of
Ac-[(S)-β3-hPhg--Oxd]6-NHCH3 at the HF/6-31G* level of ab ini-
tio MO theory.
Conclusions
In this paper, we reported the synthesis and conforma-
tional analysis of a novel class of foldamers containing
alternating (S)-β3-homophenylglycine [(S)-β3-hPhg] and -
4-carboxyoxazolidin-2-one (-Oxd) residues. These pseudo-
peptides were synthesized in the liquid phase utilizing uron-
ium salts (HATU or HBTU) as coupling agents. The exper-
imental conformation analysis performed in solution by IR,
1H NMR, and CD spectroscopy unambiguously proved
that these oligomers fold into ordered structures with in-
creasing sequence length. Theoretical calculations per-
formed by employing ab initio MO theory suggest a helix
with 11-membered hydrogen-bonded rings as the preferred
secondary structure type. A left-handed mixed helix H(11)/9
was also obtained as a conformer, but it is less stable than
the H11 hexamer and the hydrogen bond lengths are too
long, owing to steric effects caused by the oxazolidin-2-one
rings. The novel structures enrich the field of peptidic folda-
mers and might be useful in the mimicry of native peptides.
Experimental Section
General: Routine NMR spectra were recorded with spectrometers
at 400, 300, and 200 MHz (1H NMR) and at 100, 75, and 50 MHz
(13C NMR). Chemical shifts are reported in δ values relative to the
solvent peak of CHCl3 set at δ = 7.27 ppm. High quality 1H NMR
spectra were recorded with a Varian Inova 600. The measurements
were carried out in CDCl3 and in [D6]DMSO by using tetramethyl-
silane as an internal standard. Proton signals were assigned by
COSY spectra. Data for conformational analysis were obtained
from 2D NOESY spectra with typical mixing times of 0.4 s. High
quality infrared spectra (64 scans) were obtained at 2 cm–1 resolu-
tion by using a 1 mm NaCl solution cell and a Nicolet 380 FT-IR
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spectrometer. All spectra were obtained for 3 m solutions in dry
CH2Cl2 at 297 K. All compounds were dried in vacuo. Sample
preparation was performed under a nitrogen atmosphere. The melt-
ing points of the compounds were determined in open capillaries.
They are uncorrected. The CD spectra were obtained by employing
a Jasco J-810 spectropolarimeter. Cylindrical fused quartz cells of
0.02 cm path length were used. The values are expressed in terms
of the molar ellipticity [θ]T degcm2 dmol–1.
0.50 g) and Et3N (3 mmol, 0.44 mL) in dry acetonitrile (35 mL) at
room temperature. The solution was stirred for 40 min under an
inert atmosphere. Acetonitrile was then removed under reduced
pressure and replaced with ethyl acetate. The mixture was washed
with brine, 1  aqueous HCl (3ϫ30 mL), and 5% aqueous
NaHCO3 (1ϫ30 mL), and the solution was dried with sodium sul-
fate and concentrated in vacuo. The product was obtained pure
after silica gel chromatography (cyclohexane/ethyl acetate, 8:2) in
73% yield (0.55 g). M.p. 157 °C. [α]D = –11.0 (c = 1.0, CH3CN).
1H NMR (300 MHz, CDCl3): δ = 1.39 (s, 9 H, tBu), 1.46 (d, J =
5.1 Hz, 3 H, Me), 1.54 (d, J = 6.0 Hz, 3 H, Me), 3.21 (dd, J = 7.8,
13.8 Hz, 1 H, CHH-CHPh), 3.36 (dd, J = 9.9, 15.0 Hz, 1 H, CHH-
CHPh), 3.53–3.64 (m, 2 H, 2ϫCHH-CHPh), 4.27 (d, J = 4.2 Hz,
1 H, CHN), 4.50–4.56 (m, 2 H, CHN + CHO), 4.71 (dq, J = 4.5,
6.0 Hz, 1 H, CHO), 5.20 (br. s, 4 H, OCH2Ph + NH + CH2-CHPh),
5.50–5.59 (m, 1 H, CH2-CHPh), 7.21–7.40 (m, 16 H, NH + 3ϫPh)
ppm. 13C NMR (75 MHz, CDCl3): δ = 20.6, 21.0, 28.3, 29.5, 38.6,
41.3, 42.7, 50.0, 51.5, 61.6, 62.1, 67.9, 73.6, 74.1, 126.2, 127.6,
127.8, 128.2, 128.7, 128.8, 134.6, 139.6, 141.0, 152.2, 152.5, 155.2,
Boc-(S)-β3-hPhg-
D-Oxd-OBn (2): To a stirred solution of Boc-(S)-
β3-hPhg-OH (1.11 g, 4.2 mmol) in acetonitrile (150 mL) was added
HBTU (1.59 g, 4.2 mmol) followed by -Oxd-OBn (1, 1.0 g,
4.2 mmol) and finally DBU (1.25 mL, 8.4 mol). The mixture was
stirred for 45 min, and acetonitrile was then removed under re-
duced pressure. The residue was dissolved in ethyl acetate. The mix-
ture was washed with brine, 1  aqueous HCl (3ϫ30 mL), and 5%
aqueous NaHCO3 (1ϫ30 mL), and the solution was then dried
with sodium sulfate and concentrated in vacuo. Pure product 2
was obtained in 95% yield (0.89 g) as a white solid after silica gel
chromatography (cyclohexane/ethyl acetate, 8:2). M.p. 132 °C. [α]D
167.1, 167.9, 170.3, 171.1 ppm. IR (CH Cl , 3 m): ν = 3430, 3412,
˜
2
2
1
= +12.5 (c = 1.0, CH2Cl2). H NMR (300 MHz, CDCl3): δ = 1.42
1788, 1754, 1725, 1707 cm–1. C40H44N4O11 (756.80): calcd. C 63.48,
(s, 9 H, tBu), 1.53 (d, J = 6.3 Hz, 3 H, Me), 3.11–3.28 (m, 1 H,
CHH-CHPh), 3.61–3.84 (m, 1 H, CHH-CHPh), 4.42 (d, J =
4.2 Hz, 1 H, CHN), 4.55 (dq, J = 4.2, 6.3 Hz, 1 H, CHO), 5.19
(AB, J = 12.3 Hz, 2 H, OCH2Ph), 5.30 (br. s, 2 H, NH + CH2-
CHPh), 7.31–7.38 (m, 10 H, 2ϫPh) ppm. 13C NMR (75 MHz,
CDCl3): δ = 21.0, 28.3, 42.5, 51.1, 61.8, 67.8, 73.4, 79.7, 126.2,
127.6, 128.2, 128.7, 134.6, 140.9, 152.1, 155.1, 167.8, 170.3 ppm.
IR (CH Cl , 3 m): ν = 3439, 1791, 1752, 1706 cm–1. C H N O
H 5.86, N 7.40; found C 63.47, H 5.78, N 7.38.
Boc-[(S)-β3-hPhg-
D-Oxd]2-OH (6): For the synthetic procedure
from 5, see the preparation of Boc-(S)-β3-hPhg--Oxd-OH (3)
1
given above. M.p. 75 °C. [α]D = –11.7 (c = 1.0, MeOH). H NMR
(300 MHz, CD3OD): δ = 1.42 (s, 9 H, tBu), 1.51 (d, J = 6.0 Hz, 3
H, Me), 1.56 (d, J = 6.3 Hz, 3 H, Me), 3.05 (dd, J = 9.0, 14.4 Hz,
1 H, CHH-CHPh), 3.35 (dd, J = 11.1, 16.2 Hz, 1 H, CHH-CHPh),
3.56–3.66 (m, 2 H, 2ϫCHH-CHPh), 4.43 (d, J = 3.9 Hz, 1 H,
CHN), 4.53 (d, J = 3.9 Hz, 1 H, CHN), 4.59 (dq, J = 3.9, 6.3 Hz,
1 H, CHO), 4.69 (dq, J = 3.9, 6.0 Hz, 1 H, CHO), 5.18–5.22 (m, 1
H, CH2-CHPh), 5.57 (dd, J = 3.0, 11.1 Hz, 1 H, CH2-CHPh), 7.28–
7.45 (m, 10 H, 2ϫPh) ppm. 13C NMR (75 MHz, CD3OD): δ =
20.9, 21.3, 28.8, 30.5, 38.9, 43.0, 43.9, 48.2, 52.3, 63.2, 64.0, 75.7,
76.2, 80.2, 127.4, 128.3, 128.6, 129.7, 141.8, 143.4, 154.2, 154.4,
˜
2
2
26 30
2
7
(482.53): calcd. C 64.72, H 6.27, N 5.81; found C 64.69, H 6.30, N
5.86.
Boc-(S)-β3-hPhg- -Oxd-OH (3): To a solution of Boc-(S)-β3-hPhg-
D
-Oxd-OBn 2 (2.86 mmol, 1.37 g) in methanol (185 mL), was
added 10% palladium on charcoal (86 mg). The mixture was stirred
under a hydrogen atmosphere for 24 h. The catalyst was then fil-
tered through a celite pad, and the mixture was concentrated. Cor-
responding acid 3 was obtained pure in quantitative yield (1.10 g)
without any further purification. M.p. 115 °C. [α]D = +63.0 (c =
1.0, CH2Cl2). 1H NMR (300 MHz, CD3OD): δ = 1.45 (s, 9 H, tBu),
1.53 (d, J = 6.0 Hz, 3 H, Me), 3.12 (dd, J = 9.9, 14.1 Hz, 1 H,
CHH-CHPh), 3.67 (dd, J = 3.0, 14.1 Hz, 1 H, CHH-CHPh), 4.42
(d, J = 3.9 Hz, 1 H, CHN), 4.71 (dq, J = 3.9, 6.0 Hz, 1 H, CHO),
5.16–5.32 (m, 1 H, CH2-CHPh), 7.31–7.42 (m, 5 H, Ph) ppm. 13C
NMR (75 MHz, CD3OD): δ = 21.3, 28.8, 43.9, 52.4, 63.1, 75.6,
80.4, 127.5, 128.4, 129.6, 143.2, 154.2, 157.7, 171.6 ppm. IR
157.6, 170.2, 171.5, 181.5 ppm. IR (nujol): ν = 3313, 1780,
˜
1706 cm–1. C33H38N4O11 (666.68): calcd. C 59.45, H 5.75, N 8.40;
found C 59.39, H 5.73, N 8.42.
Boc-[(S)-β3-hPhg-
D-Oxd]3-OBn (7): For the synthetic procedure
from 6 and 4, see the preparation of Boc-[(S)-β3-hPhg--Oxd]2-
OBn (5) given above. The product was obtained pure after silica gel
chromatography (dichloromethane/ethyl acetate, 8:2) in 81% yield.
1
M.p. 220 °C. [α]D = –3.0 (c = 1.0, CH2Cl2). H NMR (400 MHz,
CDCl3): δ = 1.34 (s, 9 H, tBu), 1.42 (d, J = 6.0 Hz, 3 H, Me), 1.50
(d, J = 6.0 Hz, 3 H, Me), 1.54 (d, J = 6.0 Hz, 3 H, Me), 3.15–3.67
(m, 6 H, 3ϫCH2-CHPh), 4.22 (br. s, 1 H, CHN), 4.37–4.72 (m, 5
H, 2ϫCHN + 3ϫCHO), 5.07 (br. s, 1 H, NH), 5.15–5.23 (m, 3
H, OCH2Ph + CH2-CHPh), 5.45–5.50 (m, 1 H, CH2-CHPh), 5.50–
5.60 (m, 1 H, CH2-CHPh), 6.94 (br. s, 1 H, NH), 7.17 (br. s, 1 H,
NH), 7.25–7.39 (m, 20 H, 4ϫPh) ppm. 13C NMR (75 MHz,
CDCl3): δ = 20.9, 21.3, 28.5, 41.5, 42.8, 50.1, 50.7, 51.9, 62.0, 63.3,
68.2, 73.9, 74.8, 126.5, 128.1, 128.5, 129.0, 129.1, 134.8, 139.9,
152.5, 153.0, 155.6, 167.3, 168.1, 170.4, 171.6 ppm. IR (CH2Cl2,
3 m): ν = 3416, 3344, 1788, 1700 cm–1. C H N O (1031.07):
(CH Cl , 3 m): ν = 3435, 1790, 1750, 1710 cm–1. C H N O
˜
2
2
19 24
2
7
(392.16): calcd. C 58.16, H 6.16, N 7.14; found C 58.20, H 6.12, N
7.16.
TFAH-(S)-β3-hPhg-
D-Oxd-OBn (4): A solution of Boc--Ala--
Oxd-OBn (2a, 1 mmol, 0.48 g) and TFA (18 mmol, 1.38 mL) in dry
dichloromethane (10 mL) was stirred for 2 h at room temperature.
The volatiles were then removed under reduced pressure, and the
product was obtained pure in quantitative yield (0.49 g) without
any further purification. 1H NMR (300 MHz, CDCl3): δ = 1.53 (d,
J = 6.0 Hz, 3 H, Me), 3.72 (dd, J = 3.9, 18.6 Hz, 1 H, CHH-
CHPh), 3.87 (d, J = 8.1, 18.6 Hz, 1 H, CHH-CHPh), 4.43 (br. s, 3
H, NH), 4.52–4.60 (m, 2 H, CHN + CHO), 4.77 (dd, J = 3.9,
8.1 Hz, 1 H, CH2-CHPh), 5.19 (AB, J = 12.0 Hz, 2 H, OCH2Ph),
7.31–7.38 (m, 10 H, 2ϫPh) ppm.
˜
54 58
6
15
calcd. C 62.90, H 5.67, N 8.15; found C 62.94, H 5.73, N 8.09.
Boc-[(S)-β3-hPhg-
D-Oxd]3-OH (8): For the synthetic procedure
from 7, see the preparation of Boc-(S)-β3-hPhg--Oxd-OH (3)
1
given above. M.p. 177 °C. [α]D = –27.0 (c = 1.0, MeOH). H NMR
Boc-[(S)-β3-hPhg-
D
-Oxd]2-OBn (5): To a stirred solution of Boc-
(400 MHz, CD3CN): δ = 1.27 (d, J = 5.2 Hz, 3 H, Me), 1.32 (s, 9
H, tBu), 1.43–1.48 (m, 6 H, 2ϫMe), 2.80–3.18 (m, 2 H, CH2-
CHPh), 3.28–3.45 (m, 6 H, 3ϫCH2-CHPh), 4.16 (br. s, 1 H,
CHN), 4.26–4.32 (m, 2 H, CHN + CHO), 4.37–4.0 (m, 1 H, CHN),
(S)-β3-hPhg--Oxd-OH (3) (1 mmol, 0.39 g) and HATU (1 mmol,
0.38 g) in dry acetonitrile (35 mL) under an inert atmosphere was
added a mixture of H--Ala--Oxd-OBn·CF3CO2H (4, 1 mmol,
2718
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2713–2721

Alternate α,β-Hybrid Peptides Containing Oxazolidin-2-one Moieties
4.46–4.51 (m, 1 H, CHO), 4.62–4.68 (m, 1 H, CHO), 5.02 (br. s, 1 6.0 Hz, 1 H, CHO), 5.22 (br. s, 1 H, CH2-CHPh), 5.27 (AB, J =
FULL PAPER
H, CH2-CHPh), 5.31–5.46 (m, 2 H, 2ϫCH2-CHPh), 5.85 (br. s, 1
H, NH), 7.24–7.37 (m, 15 H, 3ϫPh), 7.42–7.50 (m, 2 H, NH) ppm.
12.8 Hz, 2 H, OCH2Ph), 5.48–5.66 (m, 4 H, 4ϫCH2-CHPh), 6.79
(d, J = 6.0 Hz, 1 H, NH), 7.20–7.49 (m, 30 H, 6ϫPh), 8.49 (d, J
13C NMR (100 MHz, CD3CN): δ = 19.9, 20.0, 20.4, 27.8, 41.7, = 8.8 Hz, 1 H, NH), 8.62 (d, J = 8.8 Hz, 1 H, NH), 8.70 (d, J =
41.9, 42.3, 49.4, 49.5, 51.1, 61.5, 62.7, 62.9, 74.1, 74.8, 75.0, 126.4, 8.8 Hz, 1 H, NH) ppm. 13C NMR (100 MHz, [D6]acetone): δ =
126.5, 127.5, 127.8, 127.9, 128.7, 128.9, 129.0, 141.1, 141.3, 142.6,
152.7, 153.1, 153.2, 155.4, 167.6, 167.7, 169.4, 170.0, 170.2, 71.2, 72.5, 124.0, 124.1, 124.6, 124.8, 125.0, 125.1, 125.7, 125.9,
170.3 ppm. IR (nujol): 126.0, 126.1, 126.2, 133.2, 138.8, 139.1, 149.9, 150.6, 165.2, 165.3,
3343, 1782, 1764, 1676 cm–1.
17.7, 17.8, 17.9, 25.5, 39.8, 40.0, 46.6, 59.2, 60.1, 60.2, 60.3, 65.0,
ν
˜
=
C47H52N6O15 (940.95): calcd. C 59.99, H 5.57, N 8.93; found C
59.95, H 5.60, N 8.90.
167.3, 167.4, 167.6 ppm. IR (CH Cl , 0.2 m): ν = 3306, 1779,
˜
2 2
1712, 1665 cm–1. C82H86N10O23 (1579.61): calcd. C 62.35, H 5.49,
N 8.87; found C 62.30, H 5.47, N 8.85.
Boc-[(S)-β3-hPhg-
D-Oxd]4-OBn (9): For the synthetic procedure
from 8 and 4, see the preparation of Boc-[(S)-β3-hPhg--Oxd]2-
OBn (5) given above. The product was obtained pure after silica gel
chromatography (dichloromethane/ethyl acetate, 8:2) in 80% yield.
M.p. 237 °C (dec.). [α]D = –26.5 (c = 0.2, CH2Cl2). 1H NMR
(400 MHz, [D6]acetone): δ = 1.33 (d, J = 7.2 Hz, 3 H, Me), 1.34
(s, 9 H, tBu), 1.37 (d, J = 6.0 Hz, 3 H, Me), 1.51 (d, J = 6.0 Hz, 3
H, Me), 1.55 (d, J = 6.0 Hz, 3 H, Me), 2.82–2.93 (m, 1 H, CHH-
Boc-[(S)-β3-hPhg-
D-Oxd]5-OH (12): For the synthetic procedure
from 11, see the preparation of Boc-(S)-β3-hPhg--Oxd-OH (3)
above. M.p. 274 °C (dec.). [α]D = –39.0 (c = 0.1, MeOH). 1H NMR
(400 MHz, CD3OD): δ = 1.23 (d, J = 5.2 Hz, 3 H, Me), 1.30 (d, J
= 6.4 Hz, 3 H, Me), 1.41 (s, 9 H, tBu), 1.65 (d, J = 6.0 Hz, 6 H,
2ϫMe), 3.00–3.14 (m, 1 H, CHH-CHPh), 3.32–3.75 (m, 7 H,
CHH-CHPh + 3ϫCH2-CHPh), 4.24–4.38 (m, 3 H, CHN +
CHPh), 2.93–3.50 (m, 1 H, CHH-CHPh), 3.16 (dd, J = 10.8, 2ϫCHO), 4.45 (d, J = 5.2 Hz, 1 H, CHN), 4.56 (d, J = 4.8 Hz, 1
18.4 Hz, 1 H, CHH-CHPh), 3.20 (dd, J = 11.2, 18.8 Hz, 1 H, H, CHN), 4.66–4.71 (m, 1 H, CHO), 4.78–4.83 (m, 1 H, CHO),
CHH-CHPh), 3.28 (dd, J = 10.4, 15.2 Hz, 1 H, CHH-CHPh), 3.56– 5.23 (br. s, 1 H, CH2-CHPh), 5.51–5.59 (m, 3 H, 3ϫCH2-CHPh),
3.68 (m, 3 H, 3ϫCHH-CHPh), 4.40 (d, J = 3.6 Hz, 1 H, CHN),
4.43–4.47 (m, 3 H, CHN + 2ϫCHO), 4.52 (d, J = 4.4 Hz, CHN
7.73–7.97 (m, 20 H, 4ϫPh), 7.42–7.50 (m, 2 H, NH) ppm. 13C
NMR (100 MHz, CD3OD): δ = 19.5, 23.0, 23.5, 25.8, 27.6, 63.2,
1 H), 4.60–4.63 (m, 2 H, CHN + CHO), 4.78 (dq, J = 4.0, 6.4 Hz, 70.1, 75.0, 126.1, 128.7, 139.8, 149.7, 155.4, 166.3, 170.3 ppm. IR
1 H, CHO), 5.23 (br. s, 1 H, CH2-CHPh), 5.27 (AB, J = 12.4 Hz,
2 H, OCH2Ph), 5.51–5.67 (m, 3 H, 3ϫCH2-CHPh), 6.54 (d, J =
6.8 Hz, 1 H, NH), 7.21–7.48 (m, 25 H, 5ϫPh), 8.09 (d, J = 8.8 Hz,
1 H, NH), 8.22 (d, J = 8.8 Hz, 1 H, NH), 8.26 (d, J = 8.8 Hz, 1
H, NH) ppm. 13C NMR (100 MHz, [D6]acetone): δ = 19.2, 19.5,
27.0, 37.1, 37.3, 41.2, 48.3, 60.8, 62.1, 66.6, 72.9, 74.0, 125.5, 125.6,
125.7, 126.3, 126.6, 126.7, 126.8, 127.3, 127.6, 127.8, 127.9, 151.5,
(nujol): ν = 3314, 1780, 1701, 1664 cm–1. C H N O (1489.49):
calcd. C 60.44, H 5.40, N 9.42; found C 60.41, H 5.38, N 9.37.
˜
75 80 10 23
Boc-[(S)-β3-hPhg-
D-Oxd]6-OBn (13): For the synthetic procedure
from (12) and (4), see the preparation of Boc-[(S)-β3-hPhg--
Oxd]2-OBn (5) above. The product was obtained pure after
crystallization from methanol/diethyl ether in 65% yield. M.p.
265 °C (dec.). [α]D = –133.0 (c = 0.1, acetone). 1H NMR (400 MHz,
[D6]DMSO): δ = 1.15 (d, J = 6.0 Hz, 3 H, Me), 1.21 (d, J = 6.4 Hz,
6 H, 2ϫMe), 1.25 (d, J = 6.0 Hz, 3 H, Me), 1.37 (s, 9 H, tBu),
1.44 (d, J = 6.4 Hz, 3 H, Me), 1.48 (d, J = 6.4 Hz, 3 H, Me),
3.08–3.22 (m, 6 H, 6ϫCHH-CHPh), 3.32–3.52 (m, 6 H, 6ϫCHH-
CHPh), 3.96–4.14 (m, 8 H, 4ϫCHN + 4ϫCHO), 4.15–4.26 (m, 2
H, CHN + CHO), 4.39 (d, J = 4.4 Hz, 1 H, CHN), 4.62 (dq, J =
4.4, 6.4 Hz, 1 H, CHO), 4.76–4.85 (m, 1 H, CH2-CHPh), 5.00 (AB,
J = 12.8 Hz, 2 H, OCH2Ph), 5.08–5.24 (m, 5 H, 5ϫCH2-CHPh),
7.21–7.40 (m, 35 H, 7ϫPh), 7.53 (br. s, 1 H, NH), 8.90 (d, J =
8.4 Hz, 1 H, NH), 8.94 (d, J = 8.4 Hz, 2 H, 2ϫNH), 8.97 (d, J =
8.4 Hz, 1 H, NH), 9.03 (d, J = 8.4 Hz, 1 H, NH) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 20.8 (multiple signals), 28.9, 42.7 (mul-
tiple signals), 49.0 (multiple signals), 51.9, 62.7 (multiple signals),
162.7, 166.8, 166.9, 167.4, 169.1 ppm. IR (CH Cl , 0.6 m): ν =
˜
2
2
3414, 3306, 1789, 1700 cm–1. C68H72N8O19 (1305.34): calcd. C
62.57, H 5.56, N 8.58; found C 62.53, H 5.58, N 8.53.
Boc-[(S)-β3-hPhg-
D-Oxd]4-OH (10): For the synthetic procedure
from 9, see the preparation of Boc-(S)-β3-hPhg--Oxd-OH (3)
1
given above. M.p. 250 °C (dec.). [α]D = –34.1 (c = 0.2, MeOH). H
NMR (400 MHz, CD3OD): δ = 1.23 (d, J = 5.2 Hz, 3 H, Me), 1.30
(d, J = 6.4 Hz, 3 H, Me), 1.41 (s, 9 H, tBu), 1.65 (d, J = 6.0 Hz, 6
H, 2ϫMe), 3.00–3.14 (m, 1 H, CHH-CHPh), 3.32–3.75 (m, 7 H,
CHH-CHPh + 3ϫCH2-CHPh), 4.24–4.38 (m, 3 H, CHN +
2ϫCHO), 4.45 (d, J = 5.2 Hz, 1 H, CHN), 4.56 (d, J = 4.8 Hz, 1
H, CHN), 4.66–4.71 (m, 1 H, CHO), 4.78–4.83 (m, 1 H, CHO),
5.23 (br. s, 1 H, CH2-CHPh), 5.51–5.59 (m, 3 H, 3ϫCH2-CHPh),
7.73–7.97 (m, 20 H, 4ϫPh), 7.42–7.50 (m, 2 H, NH) ppm. 13C 75.3, 126.9 (multiple signals), 129.2 (multiple signals), 142.0 (mul-
NMR (100 MHz, CD3CN): δ = 19.9, 20.0, 20.4, 27.8, 41.7, 41.9, tiple signals), 153.4 (multiple signals), 167.7 (multiple signals),
42.3, 49.4, 49.5, 51.1, 61.5, 62.7, 62.9, 74.1, 74.8, 75.0, 126.4, 126.5, 170.1 (multiple signals) ppm. IR (CH Cl , 0.2 m): ν = 3405, 3289,
˜
2
2
127.5, 127.8, 127.9, 128.7, 128.9, 129.0, 141.1, 141.3, 142.6, 152.7,
153.1, 153.2, 155.4, 167.6, 167.7, 169.4, 170.0, 170.2, 170.3 ppm.
1709, 1670 cm–1. C96H100N12O27 (1853.88): calcd. C 62.20, H 5.44,
N 9.07; found C 62.25, H 5.38, N 9.09.
IR (nujol):
ν =
˜
3314, 1780, 1701, 1664 cm–1. C61H66N8O19
Boc-[(S)-β3-hPhg-
D-Oxd]6-OH (14): For the synthetic procedure
(1215.22): calcd. C 60.29, H 5.47, N 9.22; found C 60.32, H 5.43,
N 9.20.
from 13, see the preparation of Boc-(S)-β3-hPhg--Oxd-OH (3)
above. M.p. 260 °C (dec.). [α]D = +83.3 (c = 0.1, MeOH). 1H NMR
(300 MHz, CD3OD): δ = 1.29–1.55 (m, 27 H, 6ϫMe + tBu), 3.20–
3.63 (m, 12 H, 6ϫCH2-CHPh), 4.16–4.39 (m, 8 H, 4ϫCHN +
4ϫCHO), 4.44–4.50 (m, 3 H, 2ϫCHN + CHO), 4.76–4.82 (m, 1
H, CHO), 5.04–5.20 (m, 1 H, CH2-CHPh), 4.56–4.71 (m, 3 H,
5ϫCH2-CHPh), 5.41–5.58 (m, 3 H, 5ϫCH2-CHPh), 7.21–7.49 (m,
30 H, 6ϫPh) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 20.8
(multiple signals), 29.0, 42.7 (multiple signals), 49.0 (multiple sig-
Boc-[(S)-β3-hPhg-
D-Oxd]5-OBn (11): For the synthetic procedure
from 10 and 4, see the preparation of Boc-[(S)-β3-hPhg--Oxd]2-
OBn (5) above. The product was obtained pure after silica gel
chromatography (toluene/acetonitrile, 6:4) in 70% yield. M.p.
260 °C (dec.). [α]D = –45.0 (c = 0.6, CH2Cl2). 1H NMR (400 MHz,
[D6]acetone): δ = 1.31–1.38 (m, 18 H, 3ϫMe + tBu), 1.51 (d, J =
6.0 Hz, 3 H, Me), 1.55 (d, J = 6.4 Hz, 3 H, Me), 2.81–3.08 (m, 2
H, CH2-CHPh), 3.11–3.29 (m, 4 H, 4ϫCHH-CHPh), 3.54–3.69 nals), 62.7 (multiple signals), 75.3, 126.9 (multiple signals), 127.9
(m, 4 H, 4ϫCHH-CHPh), 4.40–4.46 (m, 6 H, 3ϫCHN +
3ϫCHO), 4.52–4.61 (m, 3 H, 2ϫCHN + CHO), 4.79 (dq, J = 4.4,
(multiple signals), 129.1, 142.0 (multiple signals), 153.4 (multiple
signals), 167.7 (multiple signals), 170.1 (multiple signals) ppm. IR
Eur. J. Org. Chem. 2007, 2713–2721
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2719

C. Tomasini et al.
FULL PAPER
(nujol): ν = 3292, 1778, 1706, 1666 cm–1. C H N O (1763.76):
calcd. C 60.61, H 5.37, N 9.53; found C 60.64, H 5.38, N 9.52.
Curr. Med. Chem. 1999, 6, 905–925; f) C. Baldauf, R. Günther,
H.-J. Hofmann, Biopolymers 2005, 80, 675–687; g) C. Baldauf,
R. Günther, H.-J. Hofmann, J. Org. Chem. 2006, 71, 1200–
1208; h) C. Baldauf, R. Günther, H.-J. Hofmann, Biopolymers
2006, 84, 408–413.
˜
89 94 12 27
Theoretical Calculations: Starting point for the calculations on tri-
mers and hexamers of Boc-[(S)-β3-hPhg--Oxd]n-OH were confor-
mations of the selected helix types with the ideal backbone torsion
angles of α,β-hybrid peptide helices found in ref.[4h] The N-terminal
Boc group was replaced by an acetyl group. The C-terminus was
an N-methylamide group. The methyl substituents of the -Oxd
constituents were omitted in the calculations. The geometry of all
starting conformations was completely optimized at the HF/6-
31G* level of ab initio MO theory. The solvation influence was
estimated for an aqueous environment on the basis of the IEF-
PCM formalism in the Gaussian03 program package, which was
employed for all calculations (see Supporting Information).
[5]
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Kast, D. Seebach, Chem. Biodiv. 2005, 2, 591–632; b) P. I. Arv-
idsson, N. S. Ryder, H. M. Weiss, D. F. Hook, J. Escalante, D.
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Supporting Information (see footnote on the first page of this arti-
cle): Total energies of the various helix types and 1H NMR and
NOESY spectra for Boc-[(S)-β3-hPhg--Oxd]6-OBn.
Enantiopure β3-amino acids are available at DSM Pharmaceu-
tical Products. For example, see:a) D. Peña, A. J. Minnaard,
J. G. de Vries, B. L. Feringa, J. Am. Chem. Soc. 2002, 124,
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elli, C. Peggion, F. Formaggio, C. Toniolo, Eur. J. Org. Chem.
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Acknowledgments
[6]
G. A., G. L., and C. T. thank MIUR (PRIN 2006 “Sintesi, attività
biologica e applicazioni diagnostiche di ligandi delle integrine α-v-
β-3, α-4-β-1 e α-4-β-7”) and University of Bologna (Funds for se-
lected topics) for financial support. H.-J. H. thanks Deutsche For-
schungsgemeinschaft (Project HO2346/1-3 “Secondary structure
formation in peptides with non-proteinogenic amino acids” and
SFB 610 “Protein states of cell biological and medicinal relevance”)
for financial support.
[7]
[8]
[1] S. H. Gellman, Acc. Chem. Res. 1998, 31, 173–180.
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[2] a) D. J. Hill, M. J. Mio, R. B. Prince, T. S. Hughes, J. S. Moore,
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Received: February 14, 2007
Published Online: April 19, 2007
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